www.nature.com/articles/mp20092.pdf
FEATURE REVIEW
Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer
R Tabare ́s-Seisdedos1 and JLR Rubenstein2
1Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, CIBER-SAM, University of Valencia, Valencia, Spain and 2Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA, USA
Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying suscept- ibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson’s and Alzheimer’s disease) and cancer. Furthermore, at least seven nonprotein- coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.
Molecular Psychiatry (2009) 14, 563–589; doi:10.1038/mp.2009.2; published online 10 February 2009 Keywords: 8p; NRG1; FGF family; schizophrenia; autism; cancer
Introduction
Autism and schizophrenia are complex neuropsy- chiatric syndromes affecting between 0.3 and 0.6% of children and approximately 1% of the adult world population.1,2 These disorders are chronic, debilitat- ing conditions with profound human and economic consequences.3,4 Therefore, each discovery that further elucidates disease mechanisms, and each new molecular diagnostic test or therapeutic advance
Correspondence: Professor Dr R Tabare ́s-Seisdedos. Teaching Unit of Psychiatry and Psychological Medicine, Department of Med- icine, University of Valencia, CIBER-SAM, Blasco-Iba ́ n ̃ ez 17, 46010 Valencia, Spain and Professor Dr John LR Rubenstein. Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, CA 94143, USA.
E-mails: Rafael.Tabares@uv.es and John.Rubenstein@ucsf.edu Received 1 August 2008; revised 19 December 2008; accepted 7 January 2009; published online 10 February 2009
has the potential to improve the quality of life for many people.5,6
The assumption that neuropsychiatric disorders are phenotypically heterogeneous with overlapping find- ings suggests the participation of more than one etiological factor and pathophysiological process, some of them being partly shared across the tradi- tional classification categories.7,8 Probably, as in human cancers, the heterogeneity in clinical results and treatment outcomes stems directly from the underlying variation in disorder biology.9 It is no wonder then that this remarkable biologic hetero- geneity of autism (autism spectrum disorders), schi- zophrenia (schizophrenias) or bipolar disorder (bipolar spectrum) is intimately related to the com- plexity of the genetic control of brain development and function. For instance, several of the suscept- ibility loci and genes in these disorders play a principal role in the development, plasticity and maintenance of the central nervous system (CNS).10–13 However, the molecular mechanics, the neural
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systems and the concepts used are, with few excep- tions, excessively vague.14,15
Recognizing these limitations and approaches, we focus our attention on the 8p chromosome region for several reasons. First, human chromosome 8 spans approximately 145 million base pairs (bp), which represents between 4.5 and 5.0% of the genome. The short arm spans approximately 45.2 million base pairs and only represents 1.5% of the genome, and includes 484 genes (110 pseudogenes). Many of these genes encode proteins that control cell proliferation, apop- tosis or both, and may play important roles in several normal and pathological processes such as develop- ment or signaling in the CNS and immune response, and cancer and developmental neuropsychiatric dis- orders, respectively. Currently, it is estimated that there are approximately 41 (8.47%) genes on chromo- some 8p involved in the genetic control of cerebral development and function, and approximately 80 (15.53%) genes involved in cancer biology (see Table 1 and Supplementary Table S1 at Supple- mentary Information). It is important to bear in mind that 8p has lower rates of base pairs and genes than other chromosomal regions with significant linkage to schizophrenia (1q, 6p and 22q), autism (7q and 15q) and bipolar disorder (13q). Only 18p, associated with bipolar disorder risk, has lower rates than 8p (Supplementary Table S2). Although chromosome 8 is typical in several characteristics, such as length, gene or repeat content, a unique feature of this chromosome is a big region of approximately 15 megabases on distal 8p that appears to have a high mutation rate. Likewise, this distal subregion on 8p shows an immense divergence between human and chimpanzee, suggesting that the high mutation rates at distal 8p have contributed to the evolution of the primate brain.16 Interestingly, a high mutation rate has been associated with high homologous recombination in the human genome.17 Consequently, an extraordin- ary recombination rate could increase the duplication genetic process, and allow us a better understanding of the biological connections between 8p, cancer and mental illness at a molecular level.
Second, various studies have recently evaluated the contribution of structural variation of DNA (that is, insertions and deletions of DNA, collectively termed copy number variants (CNVs), as well as balanced rearrangements such as inversions) in the human genetic variability and in the susceptibility to com- mon and complex diseases such as cancer, obesity or neuropsychiatric disorders.18–21 Now, it seems most likely that this structural variation contributes more to genetic diversity in healthy individuals and to phenotypic variation in unhealthy individuals than single-nucleotide polymorphisms.22 Subsequently, chromosomal 8p region is one of the ‘hotspot’ regions of CNVs in the human genome, because it contains clusters of three to four copy number polymorphisms (Supplementary Table S3). Other regions were 6cen and 15q13-14, which are also related with schizo- phrenia and autism.18 Moreover, many of the genes
affected by the identified structural variants encode proteins that have been shown to mediate response to environmental challenge (‘environmental sensor genes’), such as immune response, perception of smell and perception of chemical stimuli.22,23 It is interesting to take note of the presence of olfactory dysfunction in autism24 and schizophrenia sub- jects.25,26 Furthermore, these neuropsychiatric disor- ders may be associated with various immune system anomalies.27,28 The new generation sequencing tech- nologies have detected 343 copy number variations of 146 genes on chromosome 8p. Several of these genes CNVs have been associated with schizophrenia,10 autism spectrum disorders,29 cancer21,30 and Crohn’s disease31 (for updated summary, see Supplementary Table S4). It is noted that, 8p is also enriched in single-nucleotide variants across the entire gen- ome.32,33 The short arm of chromosome 8p is one of the most enriched regions in structural and single- nucleotide variation across the human genome, but, in any case, little is known about the role of such genetic diversity in disease association.
Third, given that there are genetic factors to schizophrenia and other major neuropsychiatric disorders, the remaining questions are which are the related chromosomal regions and how will the genes be identified?34 In relation to this, 8p is among the best-supported genomic regions implicated in schizo- phrenia and bipolar risk,35–40 as well as in other important human diseases such as cancer.41,42 For example, the ‘Top Results’ list of Schizophrenia Gene Database,43,44 displaying the 27 genes most strongly associated with schizophrenia, includes three 8p genes (1st VMAT1/SLC18A1; 15th NRG1; 26th PPP3CC). It is noted that, it is the chromosome region (arm) with a greater number of schizophrenia susceptibility genes in this ranking. In addition, Bray et al.45 observed that variant(s) within 8p may modulate schizophrenia risk though a transacting effect on dystrobrevin-binding protein 1 (DTNBP1) expression. DTNBP1 is one of the best-supported susceptibility genes for schizophrenia, bipolar disorder and major depressive disorder.40,46–48 These data provide complementary evidence for chromo- some 8p as a neuropsychiatry susceptibility locus.
Fourth, the animal models of human behavioral disorders represent an obvious step forward in the arena of the study of the genetics of behavioral domains.49 We recently described a mouse mutant that lacks the Fgf17 gene (Fgf17 is a member of the fibroblast growth factor (Fgf) family of genes), which is located in 8p21.3. It has abnormalities in the patterning of frontal cortex (that is, a reduction in dorsal and dorsomedial frontal cortex (FC) and FC projections to subcortical targets, and a rostromedial shift of caudal cortical areas) and social behavior deficits.50–52 Thus, this type of developmental lesion may be a relevant mechanism for some forms of autism, schizophrenia and related syndromes.
From these observations, it is reasonable to expect that 8p chromosome, as a whole, could be a
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Table 1
Chromosome 8p as a potential hub for neuropsychiatric disorders
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8p Genes involved in cerebral development, cancer, neuropsychiatric and brain disorders
565
LOCUS GENE SYMBOL
DLGAP2
CLN8
mi r-596 ARHGEF10
8p23.2 CSMD1 (1 GENE)
NEUROPSYCHIATRIC DISORDERS
*CEREBRAL DISORDERS
CEREBRAL DEVELOPMENT AND FUNCTION
CANCER
8p23.3 (4 GENES)
8p23.1 (18 GENES)
8p22 (10 GENES)
DEFB103A MCPH1 ANGPT2 DEFB1 DEFA6 DEFA1 DEFA3 DEFB4 CLDN23 MFHAS1 mi r-597
mi r-124-1 MSRA SOX7 PINX1
mi r-598 GATA4 CTSB DLC1
mi r-383 TUSC3 MSR1 FGF20 PDGFRL MT US1 PCM1 NAT1
NAT2
PSD3
ChGn
LPL VMAT1/SLC18A1 LZTS
GFRA2 DOK2 NPM2 FGF17
mi r-320 PIWIL2 PHYHIP PPP3CC KIAAA967 BIN3
EGR3 PEBP4 RHOBTB TNFRSF10C TNFRSF10D LOXL2 NKX3-1 STC1 ADAM28 ADAM7 NEF3
NEFL GNRH1 BNIPEL PNMA2 DPYSL2 ADRA1A PTK2B CHRNA2
CLU SCARA3 PBK PNOC ZNF395 FZD3 EXTL3 HMBOX1
8p21.3 (21 GENES)
8p21.2 (13 GENES)
CNVs
8p21.1 (9 GENES)
KIF13B
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Table 1
Continued
8p12 (11 GENES)
R Tabar ́es-Seisdedos and JLR Rubenstein
GSR
WRN NRG1 FUT10 DUSP26 GPR124 EIF4EBP1 LSM1 BAG4 PPAPDC1 FGFR1
TACC1
8p11.23 (17 GENES)
ADAM9
ADAM32
ADAM5P
ADAM18
ADAM2
C8ofr4
SFRP1
mi r-486
ANK1
MYST3
AP3M2
PLAT
POLB
DKK4
CHRNB3
CHRNA6
THAP1
8p11.2- p11.1
(1 GEN)
CEBPD
TOTAL GENES
105
41
80
21
25
*Cerebral Disorders such as Epilepsy, Alzheimer Disease, Parkinson Disease, Down Syndrome and others.
Abbreviation: CNVs, copy number variants (see Ref.10).
Total number of genes on chromosome 8p = 484; genes involved in cancer = 80 (15.5%); genes involved in neuropsychiatric disorders = 21 (4.3%); genes involved in cerebral development and function = 41 (8.5%); genes involved in brain disorders = 25 (5.2%).
significant opportunity to explore the relationship among candidate genes, several neuropsychiatric disorders and other human diseases, including cancer, Parkinson’s disease and Alzheimer’s disease, and to define new pathophysiology pathways.
Therefore, the main goal of this review is to carefully provide a brief overview of previous find- ings that support the role of 8p not only in genetic susceptibility to neuropsychiatric disorders but also to human cancer. Moreover, we aimed to analyze 21 candidate genes (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LPL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) from a total of 484 genes located in this region, that may lead to expression of different neuropsychiatric phenotypes, ranging from autism to schizophrenia to affective disorders. They were identified by a systematic review in PubMed and in the Schizophre- niaGene (SZGene),43 AlzheimerGene (AlzGene)53 and Parkinson’s Disease (PDGene)54 Databases, supple- mented with a manual search of reference lists. These genes are likewise involved in the relevant metabolic pathways and some aspects of the neural develop- ment. In addition, there are seven microRNAs (miRNAs) located on the short arm of chromo- some 8. Two of these nonprotein-coding RNAs (hsa-mir-124-1 and hsa-mir-320) are most likely to
be critical in the CNS development and in various human disease states.55 We also present a new developmental animal model that establishes a relationship between a gene of this region (Fgf17) that mediates the patterning of frontal cortex, and specific components of social behavior. Finally, we discuss the pertinence of 8p to understand the biological connections between neuropsychiatric disorders and cancer.
Chromosome 8p, neuropsychiatric disorders and cancer
In recent years, as mentioned above, many studies have identified a number of liability genes for major neuropsychiatric disorders and other serious human diseases, such as cancer, that are located on chromo- some 8p. Then, an electronic search covering the period 1963–July 2008 was conducted using Medline database, supplemented with a manual search of reference lists. The diagnostic terms autism (and related disorders such as Asperger syndrome, Fragile X mental retardation, Rett syndrome, Tuberous Sclerosis Complex), schizophrenia, bipolar disorder or manic depression, depression and cancer were combined with keywords indicating chromosomal relationship and genetic analysis (chromosome 8, 8p chromosome, 8p genes, linkage and association
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genetic studies). Our electronic and manual search identified 639 references for neuropsychiatric disor- ders and 867 for cancer. Further, we used the information of three databases of genes: SZGene, AlzGene and PDGene Databases.43,53,54
Cytogenetic studies
Kallmann’s syndrome. The study of rare chromosomal or karyotypic abnormalities can provide critical information about the localization of disease genes.34 The region discussed—8p—is involved in microdeletions that are present in individuals with the Maestre de San Juan– Kallmann–de Morsier syndrome.56 This is a congenital disorder of hypothalamic function and reduced pituitary gonadotropic activity with result- ing association of hypogonadism, eunuchoidism and anosmia (or hyposmia). Anosmia is caused by a migration disturbance that affects the axon projections of olfactory neurons to brain. Franz Josef Kallmann57,58 was one of the first psychiatrists to study the genetic basis of mental disorders, and he reported some cases of schizophrenia and mental retardation in individuals with this syndrome. More recently, Cowen and Green59 have drawn attention to some parallels between schizophrenia and Kallmann’s syndrome, including the fact that olfactory dysfunctions (that is, smell identification deficits) are present in a subgroup of patients with schizophrenia.60 Versiani et al.61 also confirm the association of Kallmann’s syndrome and schizo- phrenia, and abnormalities of cognition and behavior such as learning disabilities. However, other authors consider that this association is rare and confined to olfactory dysfunction.62
Autism and other related syndromes. There are several clinical reports associating chromosomal interstitial 8p (p21-23, p12-23, p12-21.2) rearrangements (that is, translocations, inversions, deletions, duplications) with autism (reviewed by Papanikolaou et al.63). It is noted that the autistic patients of these cytogenetic studies have milder phenotypes than other reported cases with abnormalities in other chromosomes. These bands might represent a critical region for social and communication deficits indicating an autism spectrum disorder, unrecognized until 3 or more years and with a negative family history of autism.64
In a Finnish population sample,65 there is also evidence that 8p anomalies are associated with mental retardation epilepsy. The patients with mental retardation epilepsy are distinguished from the majority of epilepsy cases in that they suffer mental deterioration following the onset of seizures. More- over, the degree of mental deterioration correlates with the severity of cerebral atrophy.66 Autism includes a high prevalence of mental retardation, with rate estimates of 40–55% or higher,67 and comorbid epilepsy, observed in approximately 30%
Chromosome 8p as a potential hub for neuropsychiatric disorders
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of autistic subjects.68 Furthermore, the occurrence of schizophrenia-like symptoms and secondary affec- tive symptoms has been shown in patients with epilepsy.69 Even more interestingly, a family history of epilepsy is a significant risk factor for schizo- phrenia.70
Aberrations in the short arm of chromosome 8 may also be a relatively common cause of corpus callosum malformations.71 Moreover, 8p21-p23 is a suitable candidate locus for agenesis of the corpus callosum.72 The association of corpus callosum anomalies with cognitive deficits, epilepsy, autistic-like behavior or schizophrenia-like symptoms is relevant and well known.73 Finally, several recent studies have detected novel submicroscopic 8p abnormalities using a new generation of microarray analysis. For example, Butler et al.74 using an array comparative genomic hybridization analysis in Prader-Willi syndrome, detected that most Prader-Willi syndrome subjects had CNVs on 8p and 3q. The autistic-like symptoma- tology in Prader-Willi syndrome75 and the association with schizophrenia and affective psychosis76 are also well known.
Cancer. Despite 8p being a relatively small chromosome arm, it is one of the most frequently altered genomic regions in human cancer,41 and is also rich in candidate oncogenes and tumor- suppressor genes associated with the development of certain types of cancers (see Table 1 and TS1 at Supplementary Information). The high frequency of cytogenetic aberrations and genomic rearrangements (principally deletions and translocations) affecting 8p in lung and prostate cancers suggests that this region may harbor potential candidate genes involved in the pathogenesis of these types of cancer.77,78 However, the loss of heterozygosity involving 8p is also a common feature of the malignant progression of others, including breast cancer,79 gastric cancer,80 colorectal cancer,81 bladder carcinoma82 and hepatocellular carcinoma, especially during metastasis.83
In spite of several methodological issues and heterogeneous results, the epidemiological studies of the relationships between schizophrenia and cancer detected a reduced incidence of cancer observed in patients with schizophrenia compared with the general population (reviewed by Catts and Catts,84 Jablensky and Lawrence,85 Grinshpoon et al.86). It is intriguing that two rigorous population- based studies found a significantly lower risk of respiratory and prostate cancer in people with schizophrenia and their relatives compared with people without schizophrenia after adjustment for confounder variables.87,88 More recently, the first meta-analysis of cancer incidence rates in patients with schizophrenia, their parents and siblings has been published.89 Catts et al.89 report a discrepancy between cancer risk exposure and cancer incidence in schizophrenia, consistent with a possible genetic protective effect. Although other possible
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explanations may be involved (that is, epidemio- logical bias, cancer-protective effect of classical anti- psychotic medications, obstetric complications and lifestyle differences),90–92 the authors propose that the genetic predisposition toward schizophrenia confers genetically reduced susceptibility to cancer.
In contrast with schizophrenia, few studies have explored in detail the cancer rates in patients with autism, bipolar disorders or other neuropsychiatric disorders. However, the co-occurrence of autism spectrum phenotype and tuberous sclerosis complex has been recognized for decades.93 Tuberous sclerosis complex is an autosomal dominant inherited disorder characterized by benign tumors that form during the development (hamartomas) in various organs such as brain (known as tubers). These brain lesions are associated with epilepsy, cognitive disability and autism.94 Despite the presence of several factors among patients with bipolar disorder that might affect the risk for cancer (that is, diet, smoking and medications), several studies found a nonsignificant statistical risk for cancer.87,95 Likewise, Carney and Jones96 in a population-based controlled study found that hyperlipidemia, lymphoma and metastatic can- cer were the only medical conditions less likely to occur in persons with bipolar disorder. More recently, BarChana et al.97 found an enhanced risk for cancer among patients with bipolar disorders. However, the risk for breast cancer was higher, but not significantly, than in the general female population. Then, no firm conclusions could be drawn.
On the basis of these clinical and cytogenetic findings, there is some evidence supporting 8p as a schizophrenia/autism overlap risk region. Curiously, the autistic patients with 8p rearrangements might have a benign clinical presentation compared with other autistic cases with abnormalities in other chromosomes. In addition, the same genetic factors located in this chromosomal region might induce cancer in the general population, but have also a possible protective effect for lung and prostate cancer in individuals with schizophrenia and their relatives. In this respect, 8p may represent a landmark for the identification and cloning of genes involved in cancer, schizophrenia and others.
Linkage studies
Linkage studies have provided evidence for one or more loci in the 8p region that influence suscept- ibility to several neuropsychiatric phenotypes.
Schizophrenia. The seminal study of Pulver et al.35 and three independent investigations have reported logarithm of odds (LOD) scores above 3.038,98,99 and another four have confirmed a LOD score above 1.5.36,38,100,101 Moreover, this region is supported by the results of published meta-analyses of schizophrenia linkage studies.102,103 However, a published study has not been able to find significant evidence for linkage on 8p region.104 It is important to take into consideration that Kendler et al.105 found an
association between 8p22-21 locus and some clinical features in 265 multiplex schizophrenia pedigrees. More specifically, affected individuals from families with evidence of linkage to 8p had significantly more affective deterioration and thought disorders, a worse outcome, and fewer depressive symptoms than affected individuals from the other families in the study. Furthermore, Chiu et al.106 have also shown that schizophrenia susceptibility appears to be associated with 8p21 region in some families, where the affected siblings are more likely to have experienced bizarre delusions, attendance to a special school, affective symptoms early in the course of illness and seizures.
Affective disorders. Although chromosome 8p showed no evidence of linkage in a genome-wide linkage scan study of schizophrenia and bipolar people,102,107 five genome scan studies and one of the two published meta-analyses supports this region in bipolar disorder.108–113 Indeed, the psychotic bipolar disorder subtype was further studied in a genome-wide linkage analysis of 40 extended bipolar pedigrees (only subjects with psychotic features were considered affected), and the two strongest regions in the genome were 9q31 and 8p21.112 These findings are additionally supported by a new genome-wide linkage scan in a large bipolar disorder sample from the National Institute of Mental Health (Genetics Initiative) that found a suggestion of linkage (8p22) for bipolar patients with psychotic symptoms.114
In major depression, the 8p region is supported by two genome-wide linkage studies with partially shared samples of families with two or more probands of early-onset recurrent major depression.115–117 Zubenko et al.116 reported a positive association between a history of suicide attempts and several chromosomal regions. It is noted that the highest DLOD score (DLOD = 5.08) was located at 8p22-p21 (D8S1145; 37.0 cM, 18.2 Mbps, P < 0.0001). It is relevant to take into account that suicide is a prevalent outcome of neuropsychiatric disorders, and that repetitive, self-injurious behavior may appear in individuals with autism or related dis- orders.118,119 The other positive linkage was obser- ved in a secondary analysis after Holmans and colleagues117 controlled for the sex of affected pair. Their results suggest that the contribution of 8p loci may be sex dependent, and that 8p contains genes that contribute to susceptibility to severe and persis- tent episodes of depression.
Other neuropsychiatric disorders. Other linkage analyses have also shown linkage of other neuropsychiatric disorders and developmental cognitive deficits to chromosome 8p. Subsequently, the region has been implicated in reading disability or developmental dyslexia in individuals with attention-deficit/hyperactivity disorder,120 anxiety- related personality traits such as harm avoidance and neuroticism,121–123 late-onset Alzheimer’s disease,124
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late-onset Alzheimer’s disease with positive symptoms of psychosis125 and idiopathic late-onset Parkinson’s disease.126 In contrast with these disorders, there has been no strong evidence for linkage on chromosome 8p in any of the genome-wide linkage studies of autism.127,128 Only one linkage analysis on multiplex autism families stratified according to delayed expressive speech found higher linkage signals in the delayed groups for some loci on chromosome 8p.129
Given this linkage scenario, chromosome 8p should be considered as a robust candidate for a suscept- ibility region for schizophrenia especially with clinical features that bring to mind the classical dementia-praecox syndrome described by Emil Kraepelin.130 In addition, there is suggestive evidence for bipolar disorder with psychotic symptoms, major depression with recurrent episodes and suicide attempts, and specific anxiety-related personality traits such as neuroticism and harm avoidance, but insufficient evidence for other neuropsychiatric phenotypes, including autism, Parkinson’s disease and Alzheimer’s disease. It is noteworthy, therefore, that the 8p arm appears to increase the probability that several major neuropsychiatric disorders will show higher levels of affective severity, suicidal behavior, psychotic symptoms and poor outcome. Some aspects of this clinical variability concur in part with deficits in social cognition.119 Nevertheless, on the basis of 8p linkage findings, at least some risk genes affect, in part, the expression of specific phenotypes across the nosological boundaries.
Studies of individual genes: association, gene expression and endophenotype investigations
To our knowledge, there are 484 genes located on 8p (for exhaustive and update information about their localization and description—locus, bases, names, ID, MIM, type and ontology: functions, processes and components—see Supplementary Table S1 at Supple- mentary Information section). In recent years, as mentioned above, many studies have identified several susceptibility genes for schizophrenia and other neuropsychiatric disorders that are located on chromosome 8p. Specifically, our electronic and manual search identified 19 potential candidate genes from association studies. Following the first recom- mendation (broad view) proposed by Lohmueller et al.131 to reduce false positive associations, we consider those associations that have been replicated at least once with an independent sample. Nine genes located on 8p satisfy the criteria of Lohmueller et al.131: DPYSL2, EGR3, FGF20, FZD3, LPL, NAT2, NRG1, PPP3CC and VMAT1/SLC18A1. We also consider the current state of evidence for 11 addi- tional candidate genes that do not satisfy the Lohmueller et al. criteria, but have a significant association in only one study: ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, FGFR1, NEF3, PCM1, PLAT and SFRP1. Finally, we consider three additional genes as other potential candidate genes on
Chromosome 8p as a potential hub for neuropsychiatric disorders
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8p chromosome from molecular genetics and cerebral developmental studies: FGF17, hsa-mir-124-1 and hsa-mir-320.
Table 2 summarizes the published findings about 8p genes in neuropsychiatric disorders, highlighting results that show the relationship among this candidate genes and a number of normal and pathological conditions, such as neurodevelopmental processes, gene expression in the CNS and in the peripheral sources of patients, endophenotype inves- tigations, experimental disease models and cancer research.132–345 Other 14 genes located on 8p (ADRB3, BIN3, CLU, CTSB, EPHX2, GNRH1, NAT1, NEFL, PDLIM2, PEBP4, PIWIL2, PNOC, SLC39A14, SORBS3 and WRN) were investigated in at least one study that did not show association with neuropsychiatric disorders (see Ref.43,53,54).
A developmental animal model from 8p: potential implications for autism, schizophrenia, affective disorders and cancer
Numerous studies have reported that social cognition impairments, especially deficits in theory of mind, emotion perception and social perception, are a core of autism and schizophrenia.346–348 Although the molecular and cellular mechanisms underling social cognitive deficits have not been clarified, recent studies have linked social dysfunction changes in rodents to neurodevelopmental abnormalities asso- ciated with autism,349 depression and schizo- phrenia,350 and Rett syndrome.351 More specifically, genes involved in neurodevelopment are essential for normal social behaviors. Fgf are particularly interest- ing in this regard. Fgf genes encode a family of 22 signaling molecules, which signal through at least four FGF receptors, play a central role in development and in tissue homeostasis.158,159 Blocking Fgf receptor signaling by expressing a dominant-negative Fgf1R receptor during embryonic development resulted in decreased cortical thickness.160 Expressing the domi- nant-negative Fgf1R in dopamine neurons reduced the number of dopamine neurons, increased dopa- mine levels in the striatum and impaired prepulse inhibition,352 changes which may have relevance to the neuropathology and sensorimotor gating deficits in schizophrenia.353,354 Moreover, FGF20 at 8p21.3-22 was identified as a risk factor for Parkinson’s disease.161–164 Likewise, Murase & McKay168 showed, in vitro experiments, that FGF signals (specifically, FGF20 and FGFR1) to elevate dopamine levels and protect the specific midbrain neuron type. Because Parkinson’s disease is characterized by loss of midbrain dopaminergic neurons, it is possible that altered FGF-signaling might have permanent effects on CNS function by the dopaminergic nigrostriatal system.355,356
FGF-signaling defects are also linked to major depression. Two recent postmortem analyses, showed a reduction, on the one hand, of FGF members (FGF1, FGF2, FGFR2 and FGFR3) in the frontal cortex of
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Table 2
List of candidate 8p genes associated with neuropsychiatric disorders and investigated in several domains
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
DPYSL2
DPYSL2 is an important molecule in neurite outgrowth and in neurite degeneration, and is expressed in the developing and adult nervous systems132,133
SZ: Increase of DPYSL2 in the hippocampus134
SZ þ BD þ MD: the expression of DPYSL2 is decreased in the FC,135 and in the ACC136
SZ: 2 CCS141,142 SZ: 1 FBS143 BD: 1 FBS143
SZ: 2 CCS142,137
BD: 1 CCS144 METH psychosis: 1 CCS145
SZ: DPYSL2 is associated with paranoid type but not with hebephrenic schizophrenia141
Cancer: Goulet et al.150 found an increase of DPYSL2 expression in HCT116 colon cancer cells treated with selenomethionine, which is an anticancer drug. This finding suggests that DPYSL2 could play a functional role in the growth inhibitory effects of selenomethionine
Thepma2236T>Cin the 30 untranslated region of the DRP-2 gene has been shown to be a negative genetic risk factor for paranoid-type schizophrenia.141 However, Hong et al.142 found that the DRP-2 a2236 C allele may influence susceptibility to Schizophrenia
8p21.2a
EGR3a 8p21.3
EGR3 is a zinc-finger transcription factor and plays important roles in cellular growth and in neuronal development. For example, EGR3 may be a critical regulator of endogenous GABRA4 during development151
SZ þ BD: EGR3 mRNA levels were decreased in the DLPFC of schizophrenic, but not bipolar subjects152
SZ: 1 CCS152 SZ: 1 FBS152
DM: Evidence for support a role for BDNF as the mediator of EGR3-induced GABRA4 regulation in developing neurons and epilepsy154
Cancer: Suzuki et al.157 showed an estrogen- mediated induction of EGR3 in breast carcinoma cells. EGR3 also plays an important role in estrogen-meditated invasion and is an independent prognostic factor in breast carcinoma
There are only two published studies that have reported involvement of EGR3 in neuropsychiatric disorders.
FGF20a 8p22
Fgf genes play a central role neuronal development158–160
PD: 1 CCS161 PD: 3 FBS162–164
PD: 2 CCS165,166 SZ: 1 CCS167
DM: Murase and McKay168showed, in vitro experiments, that FGF signals (specifically, FGF20 and FGFR1) to elevate dopamine levels and protect the specific midbrain neuron type
Cancer: members of the Fgf family are associated with a variety of human cancers169–171
bMeta-analysis of all published PD- association studies (4 CCS) for rs1989754 pm (OR (95% CI) = 1.04 (0.86, 1.27))
FZD3a 8p21.1
Wnt-Fz is a ligand-receptor pair with a conserved role in neuronal process development. For example, FZD3 activity mediates Wnt-dependent neurogenesis and neurite outgrowth173–175
BD: FZD3 mRNA levels were decreased in the orbitofrontal cortex of bipolar subjects176 BD: FZD3 has been identified as a biomarker for high mood in whole-blood (predominantly lymphocytes) samples177
SZ: 2 CCS178,179 SZ: 1 FBS180
SZ: 4 CCS181–184 SZ: 3 FBS181,185,186
DM: Inactivation of Fz3 in mice causes the absence of, or a great reduction in, several axon tracts, including the anterior commissure, corticospinal tract, corpus callosum, fornix, thalamocortical and corticothalamic tracts, stria medullaris, stria terminalis and hippocampal commissure. Thus, Frizzled3 plays an important
Cancer: Wnt path way- related genes are associated with cancer.189 For instance, Frizzled could play a role in the invasive migration of melanoma cancer cells through noncanonical Wnt5a signaling pathway.190
bThree meta-analyses of the published SZ- association studies:
5 CCS for rs960914 pm (OR (95% CI) = 0.91 (0.77, 1.08))
SZ: no differences in DPYSL2 expression at lymphocytes137 AD: Decrease of DPYSL2 in the hippocampus138
DPYSL2 expression in the
DS: Dysregulation of DPYSL2 protein and decrease of mRNA in brain139,140
DM: DPYSL2 is a marker for escitalopram resistance in stress model of depression147
SZ: Expression of EGR3 was significantly lower in the hippocampus of schizophrenic smokers compared with control smokers153
DM: EGR3/ mice display abnormalities in social and aggressive behavior, and defects in synaptic plasticity.155 The aggression of EGR3/ mice was reversible by treatment with clozapine, an antipsychotic drug156
The findings to date need to be confirmed by replication in other populations and methods
BD: 1 CCS183 MD: 1 CCS183
DM: Deregulation of
brain upon aging of
transgenic mouse models of AD146
CR: Several clinical studies have described a variety of neurodevelopmental abnormalities in subjects with defects of DPYSL2148,149
bMeta-analysis of all published SZ- association studies (4 CCS) for rs17666 (a2236T > C) pm (OR (95% CI) = 1.06 (0.68, 1.65))
FGF20, JAG1 and DKK1 are target genes of the Wnt–catenin signaling cascade172
FZD3 exhibited significantly increased
6 CCS for rs2241802 pm (OR (95% CI) = 0.98 (0.89, 1.07))
4 CCS for rs352203 pm (OR (95% CI) = 0.94 (0.83, 1.07))
Using a mathematical
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Table 2
Continued
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
LPL
LPL is one gene involved in lipid metabolism193
LPL plays an important role in the modifiability of neuronal response plasticity ‘‘Metaplastic control’’194
AD: a common polymorphism in the lipoprotein lipase gene modulates the risk level for sporadic AD in the eastern Canadian population but more importantly, indirectly modulates the pathophysiology of the brain in autopsy-confirmed cases195 SZ: changes in LPL expression in the DLPFC of schizophrenic subjects196
AD: 6 CCS195,197–200
AD: 6 CCS198,201–205
Lipoprotein lipase gene might influence in the differential lipid response to treatment with antipsychotic drugs206 Decreased lipoprotein lipase as a risk factor for atypical neuroleptic-induced hypertriglyceridemia207 Relation between gene of lipoprotein-lipase and life duration in patients with chronic cerebral ischemia208
Cancer: Thomassen
et al.209 suggest that LPL and EPHX2 at 8p21-22 are candidate metastasis suppressor genes in breast cancer.
LPL was found to be promising biomarker candidates for the detection of hepatocellular carcinoma210
LPL deletion is associated with prostate cancer211
bTwo meta-analyses of the published AD- association studies:
3 CCS for rs320 (HindIII) pm (OR (95% CI) = 0.73 (0.59, 0.9))
8p21.3
NAT2
NAT2 is one of two N-acetyl transferase isoforms expressed in humans, which are involved in the detoxification of heterocyclic or aromatic amines and their metabolites212
SZ: 1 CCS212 AD: 2 CCS213,214 PD: 8 CCS215–222
AD: 3 CCS223–225 ADþPD with Dementia226
PD: 6 CCS227–232 PD: 1 FBS233
Variants in NAT2 are associated with the risk to develop systemic lupus erythematosus234
Cancer: The NAT2 slow acetylator phenotype is associated with an increased risk of bladder cancer (owing to decreased detoxification of carcinogens from tobacco smoke), but has been associated with decreased risk of colorectal cancer (owing to reduced activation of carcinogens).235
8p22
NRG1a 8p12
NRG1 is the member of a family of proteins that exert a key role in neurodevelopmental processes and synaptic plasticity, including neuronal migration and specification, oligodendrocyte development, and regulation of acetylcholine, GABA and glutamate237–239
SZ: Type I NRG1 mRNA was found to be upregulated in the DLPFC and in the hippocampus of patients.241,242 Further, Hashimoto et al.241 showed that Type I NRG1 expression positively correlates with antipsychotic medication dosage.
SZ: 19 published CCS (see Ref. 43) SZ: 11 FBS (see Ref. 43)
BD: 3 CCS249–251 BD: 1 FBS251 ADP: 1 FBS125
SZ: 10 published CCS
SZ þ SZ-Rel: Gruber et al.255 found a link between NRG1 genetic variation and hippocampal volume reductions in schizophrenic patients and nonaffected relatives (SMRI)
Cancer: Overexpression of NRG1 is found in many different cancer types and correlates with cancer progression and an aggressive phenotype.260 Overexpressed NRG1 in cancers may function as oncogenes and promote cancer development by
SZ: Three published meta-analyses showed a strong positive association for six pm and the at-risk haplotypes in
Specific genetic variation in NRG1 is associated with reduced white
SZ: NRG1-ICD protein levels were increased in prefrontal
bEight meta-analyses of the published SZ- association studies:
(see Ref. 43)
SZ: 9 FBS (see Ref. 43) BD: 3 FBS143,252,253
AUT: 1 FBS254
role in outgrowth and/or guidance axonal187,188
expression in patients with ulcerative colitis191
approach for testing genetic epistasis underlying complex diseases, Kang et al.192found an interactive effects for SZ among variants of the genes NRG1, G72 (13q34), the regulator of G-protein signaling-4 (RGS4, 1q21–q22) and FZD3
SZ: Specific NRG1 risk allele was associated with poorer premorbid social functioning and with the
NRG1 with schizophrenia261–264
NAT2 with other cancers such as brain tumors, prostate cancer, bladder cancer and breast cancer236
5 CCS for rs328 (S447Ter) pm (OR (95% CI) = 0.83 (0.88, 1.04))
572
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Table 2
Continued
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
PPP3CC
PPP3CC is expressed in the rodent brain (hippocampus and cerebellum). The data suggest a potential importance of calcineurin in neurodevelopment.265
SZ: PPP3CC mRNA levels were decreased in the hippocampus of schizophrenic patients.269
SZ þ BD: PPP3CC mRNA levels in the DLPFC did not differ among schizophrenics, bipolar and controls.270
SZ: 2 CCS273,274 SZ: 2 FBS270,75 BD: 1 CCS276
SZ: 3 CCS277–279 SZ: 2 FBS143,278 BD: 1 FBS143
DM: CNB knockout mice exhibited increased locomotion, defects in social interaction, impaired prepulse and latent inhibition, and severe working/episodic-like memory deficits. These behavioral abnormalities reminiscent of both schizophrenia and bipolar phenotype.280,281
Cancer: Expression of
bMeta-analysis of all published SZ- association studies (5 CCS) for rs2461491 pm (OR (95% CI) = 1.06 (1.01, 1.12))
8p21.3
PPP3CC was significantly
matter density and connectivity in the anterior limb of the internal capsule of human brains using DTI240
cortex of patients243
SZ: Evidence of increased NRG1 signaling and/or function was found in the prefrontal cortex of patients244 SZ: Petryshen et al.245 reported an increased expression of SMDF, a type III isoform, in the PBLs of patients compared with their unaffected siblings SZ: NRG1 mRNA expression in PBLs was also lower than that in siblings and healthy controls. This expression was gradually increased in antipsychotic treated patients246
SZ: NRG1 GGF2 isoform showed a lower expression in immortalized lymphocytes of SZ patients before and after olanzapine stimulation. In contrast, NRG1 GGF isoform showed no significant difference between patients and unrelated-family controls247
SZ þ BD þ MD: Bertram
et al.248 found a reduced number of NRG1 inmunoreactive neurons in the brain of schizophrenic and depressive patients
different trajectories of change in lobar volumes of COS subjects, using SMRI256 SZ: Specific NRG1 risk allele predicts conversion to psychosis, abnormal activation of frontal and temporal lobes, and cognitive impairment in individuals at high genetic risk of schizophrenia.249
BD þ SZ: Green et al.249 found that variations in NRG1 may exert a specific effect in bipolar subjects with mood-incongruent psychotic features, as well as in schizophrenia cases that had experienced mania. Similar findings have been found by WalssBass et al.258 BDþSZ: A new NRG1 marker risk was associated with a ‘‘typical’’ bipolar I phenotype characterized by excellent recovery between episodes and no mood incongruent psychotic features.251
DM: NRG1 knockout mice exhibited hyperactivity and defects in social interaction domain (aggressive behavior and behavior response to social novelty) rather than in emotional/anxiety domain259
regulating tumor suppressor genes and/or genes that control cell differentiation or apoptosis261
Cancer: also see Discussion section
4 CCS for rs10503929 pm (OR (95% CI) = 0.87 (0.79, 0.97))
19 CCS for rs35753505 (SNP8NRG221533) pm (OR (95% CI) = 1.04 (0.96, 1.12))
6 CCS for rs3924999 (Gln38Arg) pm (OR (95% CI) = 0.96 (0.88, 1.04))
4 CCS for rs4733376 pm (OR (95% CI) = 1.08 (0.94, 1.24))
12 CCS for rs6994992 (SNP8NRG243177) pm (OR (95% CI) = 1.01 (0.94, 1.10))
4 CCS for SNP8NRG221132 pm (OR (95% CI) = 0.92 (0.83, 1.03))
12 CCS for SNP8NRG241930 pm (OR (95% CI) = 0.95 (0.87, 1.04))
5 CCS for SNP8NRG433E1006 pm (OR (95% CI) = 1.04 (0.83, 1.30))
Calcineurin may play important roles in neuroplasticity and neuronal adaptation.266 Calcineurin has been implicated in neurodegenerative disorders.267 For instance, in PD268
SZ: No significant differences were found in PPP3CC protein levels either in the prefrontal or in the hippocampus of schizophrenia patients compared with matched control subjects.271
SZ: Expression of PPP3CC gene in the whole-blood sample was not altered in patients with schizophrenia relative to control subjects272
SZ: variations on PPP3CC gene, including rs2461491, showed significant associations with the subgroup of schizophrenia with deficits of sustained attention and the executive functioning (CPT, WCST)275
downregulated in
prostate cancer and in
recurrent prostate cancer283,284
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Table 2
Continued
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
VMAT1/ SLC18A1a 8p21.3
VMAT1 might be important neuronal migration, development of neurosecretory pathways, and the neuronal survival284–286
SZ: 5 CCS published with positive results287–291 BP: 1 CCS292 AX: 1 CCS293
SZ: 1FBS291
Studies in vitro have shown that lithium and valproate increased the VMAT1 expression in nerve growth factor-differentiated PC12 cells, suggesting that this gene might be a rational target for mood drugs294
Cancer: VMAT1 might be related with human neuroendocrine tumors, such as endocrine tumors of the gastrointestinal tract and pancreas296
bMeta-analysis of all
ADRA1Aa 8p21.2
The adrenergic system regulates key biological processes that are often dysregulated in these severe mental disorders such as sleep, learning, memory, attention, arousal and adaptation to stress298
SZ: 1 CCS311 SZ: 1 FBS (trend155) AD: 1 CCS (trend312)
SZ: 3 CCS313,314 BD: 1 FBS155
The a1-adrenergic subtypes have effects on the cognitive functions of prefrontal cortex relevant to schizophrenia in animals316,317
Cancer: The selective a1 adrenergic receptor antagonist doxazosin (Dox) has been reported to inhibit prostate cancer proliferation318
ARHGEF10
ARHGEF10 is a myelin-related gene, involved in myelin structure, composition, development or maintenance308 The Rho GTPases are the molecular regulators of the cell motility processes and are involved in cell-cycle progression and gene transcription309
SZ: 1 CCS167
Cancer: Alteration in the expression pattern of ARHGEF10 in retinoblastoma tumors309
8p23.3
CHRNA2a 8p21.2
Nicotinic acetylcholine receptors (nAChRs) constitute a heterogeneous family of ion channels that mediate fast synaptic transmission in neurons. They have also been found on non- neuronal cells such as bronchial epithelium and keratinocytes
SZ: 1 FBS311 BD: 1 FBS312
SZ: 1 CCS313 SZ: 1 FBS143 BD: 1 CCS314 BD: 1 FBS143 AD: 3 CCS315–317
Nocturnal frontal lobe epilepsy is associated with variations in CHRNA2 gene318
Cancer: Mesothelioma cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) have a proliferative effect and antagonists (i.e. curare or a-cobratoxin) have an inhibitory effect. Furthermore, apoptosis mechanisms are under the control of the cholinergic system319,320
The significant association did not reach gene-wide significance after correction by permutation.312
New evidence reinforces interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets321
The cellular roles of non-neuronal nAChRs, including regulation of cell proliferation, angiogenesis, apoptosis, migration, invasion and secretion310
SZ: The PPP3CC gene expression level was positively correlated with the BPRS score272
CR: The JARID1C-regulated genes SCN2A, CACNA1H, BDNF and SLC18A1 have been associated with autism and cognitive dysfunction295
Two SZ-association studies found a gender- by-genotype effect for SZ288 and for AX293 significant differences were observed in females, but not in males
Dox treatment inhibits proliferation and induces apoptosis in breast cancer cells in vitro319
published SZ-
association studies (4
CCS) for rs2270641
(A277C) pm (OR (95%
CI) = 1.63 (1.03, 2.57))
AX: 5 positive linkage studies121–123,297
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Table 2
Continued
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
CHRNA6a 8p11.23
See CHRNA2 annotation
SZþBD: 1 FBS322
BD: 1 FBS312 AD: 3 CCS315–317
Cancer: Lam et al.323 found that nonsmall-cell lung cancers from nonsmokers showed higher expression of nAChR 6 (P < 0.001) and 3 (P = 0.007) subunit genes than those from smokers, adjusted for gender
CHRNB3a 8p11.23
See CHRNA2 annotation
SZþBD: 1 FBS322
SZ: 1 FBS143 BD: 2 FBS143,312
Cancer: Analysis of 28 aqueous cell lung carcinomas showed increased levels of 5 and 3 nAChR mRNA324
DKK4
DKK4 is involved in embryonic development through its interactions with the Wnt signaling pathway325
SZ: 1 CCS186 SZ: 1 FBS186
Cancer: the loss of DKKs may facilitate tumorigenesis. DKK4 was frequently silenced in endometrial cancer326 and colorectal cancer327
8p11.23
FGFR1a 8p12
See FGF20 annotation
MD: FGFR1 was upregulated in prefrontal cortex.328 FGFR1 was also observed to be upregulated in hippocampus.329
SZ: 1 CCS167
See FGF20 annotation. The fibroblast growth factors are potent angiogenic inducers in the embryonic brain and might play a principal role in the formation of the vascular cancers330
PCM1
The gene PCM1 is involved in the maintenance of centrosome integrity and the regulation of the microtubule cytoskeleton. Its protein structure bears similarities to the structural myosin proteins, which are microtubule-associated proteins involved in axon guidance, synaptogenesis, functioning of the synapse, and intracellular transport along axons and dendrites331
SZ: 1 CCS332 SZ: 1 FBS332
SZ: variations on PCM1 gene are associated with orbitofrontal gray matter volumetric deficits (SMRI)332
Cancer: Alterations in PCM1 structure are associated with diverse myeloid malignancies334
8p22
PLAT
The plasmin genes are involved in the degradation of Ab peptides, the accumulation of which in brain is a hallmark of AD334
AD: 1 CCS334
AD: 2 CCS334,335 AD: 1 FBS334
Cancer: PLAT is associated with oligodendrogliomas336
bMeta-analysis of all published AD- association studies (3 CCS) for rs4646972 (Alu ins/del) pm (OR (95% CI) = 1.34 (0.78, 2.31))
8p11.23
BD: FGFR1 has been identified as a biomarker for low mood in whole-blood (predominantly lymphocytes) samples177
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Table 2
Continued
Gene symbol position
Neurodevelopmental (or biological) process
Expression in the CNS and in peripheral sources of patients
Positive studies
Negative studies
Other studies (endophenotype investigations, disease models, case reports)
Cancer
Commentaries
SFRP1
Secreted frizzled related protein 1 (SFRP1) and Wnt signaling in innervated and denervated skeletal muscle337
SZ: 1 FBS186
SZ: 1 CCS186
Cancer: The frequent methylation and silencing of Wnt antagonist genes (i.e., SFRP family genes) in HCC, and suggest that their loss of function contributes to activation of Wnt signaling during hepatocarcinogenesis338 SFRP1 was shown to be hypermethylated in renal cell carcinoma and other cancer types339
8p11.23
FGF17a 8p21.3
See FGF20 annotation FGF-signaling, through FGF8, FGF15, FGF17, has a fundamental role in controlling the size of the frontal cortex340–342
DM: Fgf17-null mice showed specific social behavior deficits52
Cancer: see FGF20 and FGFR1 annotations and Discussion section
NEF3a 8p21.2
NEF3 belongs to the dopamine receptor interacting protein (DRIP) gene family. DRIP family affects many aspects of dopamine receptor activity343,344
SZ: 1 FBS143 BD: 1 FBS143
Association of NEF3 with early response to antipsychotic medication344
Cancer: NEF3 has been suggested to be potentially involved in pancreatic cancer development and progression345
mir-124-1
hsa-mir-124-1 are most likely to be critical in the CNS development55
Cancer: see Discussion section
8p23.1
mir-320
hsa-mir-320 are most likely to be critical in the CNS development55
Cancer: see Discussion section
8p21.3
Abbreviations: ACC, anterior cingulate cortex; AD, Alzheimer’s disease; ADP, Alzheimer’s disease families with psychoses; AUT, autism; AX, anxiety-related personality traits; BD, bipolar disorders; BPRS, the Brief Psychotic Rating Scale; CR, case reports; DLPFC, dorsolateral prefrontal cortex; DM, disease model; DS, down syndrome; DTI, diffusion tensor imaging; CCS, case–control Studies; COS, childhood-onset schizophrenia subjects; CPT, continuous performance test; CNS, central nervous system; FBS, family-based studies; FC, frontal cortex; GABRA4, GABA(A) receptor, a4 subunit gene; MD, major depression; METH, Methamphetamine-induced psychosis; OR, odds ratio; PBL, peripheral blood leucocytes; PD, Parkinson’s disease; pm, polymorphism; SMDF, sensory and motor neuron derived factor NRG1 isoform; SMRI, structural magnetic resonance imaging; SZ, schizophrenia; SZ-Rel, relatives of subjects with schizophrenia; WCST, Wisconsin Card Sorting Test.
Official gene symbols are reported, according to the Entrez gene database (http://www.ncbi.nlm.nih.gov/sites/entrez (last accessed 29 June 2008)). aIndicates genes that are expressed in the CNS (see Supplementary Table S5 for more information).
bIndicates odds ratio estimates by SZGene, AlzGene and PDGene databases.43,53,54 (last accessed 26 July 2008)].
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major depressed subjects compared with control and bipolar subjects357 and, on the other, of FGFR2 in the temporal cortex of major depressed subjects com- pared with control,358 although this finding has been challenged by the findings of a separate study using prefrontal postmortem cortices.328 In this last study, however, FGFR1 was upregulated in subjects with major depression or suicide. FGFR1 was also ob- served to be upregulated in hippocampus of subjects with major depression when compared with con- trols.329 The FGF system is also modulated by psychotropic drugs, including fluoxetine, diazepam and the atypical antipsychotic clozapine.359
FGF-signaling, through FGF8, FGF15, FGF17, has a fundamental role in controlling the size of the frontal cortex.340,341 Recently, we described a Fgf17/ mutant mice that showed a reduction in the size of dorsome- dial prefrontal areas and a circumscribed set of higher order social deficits, without affecting olfaction, pheromone responses, aggression or an array of nonsocial behaviors.50–52,360
In the analysis of the Fgf17/ mice, the authors used a panel of gene expression markers to examine the role of Fgf17 in the regionalization of the rodent FC. They reported that the dorsal FC of Fgf17/ mice was reduced in size, whereas ventral and orbital FC regions appeared normal. Thus, in addition to an overall effect on neocortical patterning, Fgf17 has an unexpectedly selective role in regulating dorsal FC development.50,51,360 The reduction in the dorsal FC area was complemented by a rostromedial shift of caudal cortical areas. These changes in regionaliza- tion persisted into adulthood and were accompanied by a reduction in FC projections to subcortical targets. This reduction of prefrontal cortex output to striatal or midbrain dopaminergic neurons may have impor- tant physiologic ramifications for the regulation of neural pathways involved in reward, cognition and social behavior.361
It has long been known that dorsal and ventral FC subdivisions have distinct roles in regulating cognition and behavior in rodents and primates, including humans.361,362 For example, subdivisions of the dorsal prefrontal cortex are implicated in working memory, attention, response selection, temporal processing of information, effort-related decision making and social valuation, whereas ventromedial and orbital subdivisions are implicated in behavioral flexibility, emotional regulation, delay- related decision making, evaluation of rewards and autonomic control.363 Therefore, the Fgf17/ mutant mice provide an opportunity to examine the behavioral and neurophysiologic consequences of an early developmental genetic lesion that selectively affects the dorsal FC. We propose that elucidating the signaling pathways downstream of Fgf17 will provide important insights into the genetic path- ways that regulate FC development and that may be disrupted in disorders that affect cognition, emotion and social interactions, such as autism and schizophrenia.
In addition, members of the fibroblast growth factor family are significantly associated with a variety of human cancers.169–171 For example, FGF17and FGFR1 are commonly overexpressed in advanced human prostate cancer.364,365 It is noted that there is evidence of a selective overexpression of FGFR1 and FGFR4 in clinical prostate cancer, which specifically supports the notion of targeted inhibition of these receptors to disrupt FGF signaling.366 Moreover, fusions between FGFR1 and several genes have been identified in the hematologic malignancy 8p11 myeloproliferative syndrome.367 Consequently, the above mentioned relationship between certain types of cancer invol- ving 8p and schizophrenia could be in part explained, thanks to the potential function of FGF17/FGFR1 in tumorigenesis and in cerebral development.
Discussion
Chromosome 8p is rich in genes that are implicated in neuropsychiatric disorders. VMAT1/SLC18A1, NRG1, PPP3CC and DPYSL2 are clearly associated with schizophrenia and probably with bipolar disorder. In addition, findings reveal that EGR3 (schizophrenia or SZ), FGF20 (Parkinson’s Disease or PD), FGFR1 (SZ), LPL (Alzheimer’s Disease or AZ), NAT2 (PD) and PCM1 (SZ) seem to be promising candidate genes as well, while FZD3 (SZ, bipolar disorder or BD and major depression or MD) and NAT1 (SZ, BD, PD and AZ) mainly gave negative results (see Ref.55,65,66 and Table 2). As discussed above, we suggest that alterations in FGF17, hsa-mir-124-1 and hsa-mir-320 should be considered to endow susceptibility to mental illness.
It is clearly premature to conclude that many of the 8p genes are connected to mental illness. Associa- tions with mental illness and variants on ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, LDL, PLAT and SFRP1 are weak (based only in one molecular genetics study) or contradictory (studies with positive and negative results). In addition, meta- analysis has only been performed on polymorphisms of DPYSL2, FZD3, NRG1, PPP3CC, VMAT1/SLC18A1, FGF20 and LPL, and many of these meta-analysis results may represent false-positive findings, in particular those based on small ( < 10) sample size.44
Despite the shortcomings of much of the evidence, it is worth continuing positional and association studies to scrutinize 8p, but using larger samples of different ethnic populations and more stringent criteria for replication or low P-values, focusing on those findings that have been previously repli- cated.131,368 Toward this goal, various genome-wide association studies are being applied to identify and characterize single-nucleotide polymorphisms in the DNA of hundreds or thousands of people worldwide with and without a particular disease or families with schizophrenia279 or bipolar disorder.369 Likewise, several genome-wide association studies have found that other forms of genetic variation on 8p, beyond the single-nucleotide scale, such as structural variations
Molecular Psychiatry
are associated with autism29 and schizophrenia10 among other disorders.370 Surely, these technologies are revolutionizing the genetics of behavioral traits, complex disorders or our individuality.368
Cancer and Schizophrenia: tumor-suppressor genes, oncogenes and microRNAs
Tumor-suppressor genes and oncogenes on 8p. There is considerable evidence that suggests mechanistic connections of genes on 8p among certain types of cancer and schizophrenia. It is biologically plausible that specific tumor-suppressor genes on 8p, that are downregulated in lung and prostate cancer, could be upregulated in schizophrenia. This phenomenon has been considered for various tumor-suppressor genes, such as TP53 on 17p13,371 APC or adenomatous polyposis coli on 5q21-22.372 and TGFBR2 or transforming growth factor-b receptor on 3p22, however in this last case with negative association for 10 single-nucleotide polymorphisms in the Japanese population.373
The tumor-suppressor TP53 gene has been identi- fied as the most commonly mutated gene in human neoplasms.374 The p53 tumor-suppressor protein regulates the cell cycle, checkpoint control, repair of DNA damage and apoptosis,375,376 and several devel- opmental processes, including cerebral vasculariza- tion,377 neurogenesis and neural crest migration.378 Independent genetic evidence for TP53 as a schizo- phrenia susceptibility gene is strong, with five of six studies reporting significant association.379–383 Geno- type and allele frequencies at MspI polymorphisms of TP53 are likewise significantly different between Korean schizophrenia and lung cancer subjects.371
TP53 activates the transcription of PTEN (tumor- suppressor phosphatase with tensin homology), and therefore functions as a negative regulator of the entire phosphatidylinositol-3-kinase (PI3K)-AKT sig- naling pathway that drives tumorigenesis384 and many critical signaling systems involved in neural development, survival and plasticity.385 The inap- propriate inhibition of PI3K-AKT pathway has been associated with diseases as diverse as diabetes and schizophrenia.386,387 Deregulation of PTEN function is also implicated in autism and brain tumors.388,389 It is noted that the NQO1 enzyme protects against oxida- tive stress and carcinogenesis, including stabilization of TP53.390 NQO1*2 is a missense variant (NP_000894:p.187P > S) that predicts poor survival among women with breast cancer mediated, in part, by TP53-linked roles of NQO1.391 Even more interest- ingly, one study suggests an increased risk for tardive dyskinesia in schizophrenic NQO1*2 carriers.392 Nevertheless, other studies failed in finding this association.393,394
Defects in tumor-suppressor APC gene, which is associated with colon and other cancers,395,396 are also associated with susceptibility to schizophrenia; furthermore, APC is upregulated in patients with schizophrenia.372 APC is a key component of the Wnt/
Chromosome 8p as a potential hub for neuropsychiatric disorders
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Winless signaling transduction pathway, which plays important roles in a number of developmental processes and in tumorigenesis.171,397 Thus, there may be a relationship between the functions of these tumor suppressors and the molecular mechanisms and cellular biology underlying schizophrenia.
Unfortunately, almost nothing is known about the role of 8p tumor suppressors in schizophrenia or other neuropsychiatric disorders. On the other hand, there are many putative mental illness susceptibility genes on 8p (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL mir-124-1, mir-320, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) involved in both cancer and neuropsychiatric disorders’ biology (see Table 1 and TS1 at Supplementary Information). NRG1, without a doubt, is one of the most frequently studied genes in schizophrenia (see Table 2).237,398 Over the course of last two decades, numerous investigators have tried to unravel the biological function of the NRG1 and of other related molecules (that is, of its receptors, the Epidermal Growth Factor Receptor/ErbB family of proto-oncogenes which signal in part through PI3K- AKT-PTEN) in the human brain and cancer.399 These genes have critical functions in many aspects of neural development and function.247 Furthermore, overexpression of NRG1 is found in many different cancer types and correlates with cancer progression and an aggressive phenotype,260 where it may regulate tumor-suppressor genes and/or genes that control cell differentiation or apoptosis.261 Another attractive hypothesis is that the NRG1 locus is broken in several types of epithelial cancers, such as breast, pancreatic or colon cancer.400 It is possible that most of these breaks represent chromosome translocations, but accompanied by variable amplifications, deletions and inversions proximal to these breakpoints.401
The breakage of NRG1 might have many complex effects, because there are multiple splice forms of NRG1 with different activities. In this regard, Tan et al.402 suggest that genetic regulation of NRG1 type IV isoform may have the dual effect of both protecting against cancer while increasing the risk for schizo- phrenia. Therefore, the schizophrenia risk-associated single-nucleotide polymorphism, rs6994992, which is a functional promoter variant associated with schizophrenia genetic predisposition and NRG1 type IV expression,403 might be as a negative regulator of tumorigenesis. Subsequently, Kanakry et al.404 using a B lymphoblast cell model, showed that NRG1 regulates cell adhesion by ErbB2/PI3K-AKT pathways. The cell lines derived from patients with schizophrenia showed a deficiency in NR1a-induced adhesion, suggesting a cellular phenotype that could contribute to disease risk. Nevertheless, evidence for a cosegregation of cancer with susceptibility or protective NRG1 variants for specific neuropsychia- tric disorders has not been reported; this would be more persuasive evidence for the link between these disorders.
577
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miRNAs on 8p. miRNAs play critical roles in the regulation of gene expression by translational or post translational mechanisms, and influence human genetic variation and normal development.55 miRNA expression can be dysregulated in tumor cells.171,405,406 Lujambio et al.407 have observed that DNA hypomethylation induces a loss of miRNA expression in cancer cells, such as the 8p brain- specific miRNA miR-124a. The authors functionally linked the epigenetic loss of miRNA-124a expression with the activation of oncogenes (CDK6 (cyclin D kinase 6)) and tumor-suppressor genes (Rb (retinoblastoma)). Moreover, miRNA-124a may be also deregulated in subjects with acute myeloid leukemia.408 Most recently, Silber et al.409 have shown that miRNA-124 and miRNA-137 can induce neuronal differentiation of oligodendroglioma tumor stem cells and glioblastoma multiforme (GBM) stem cells, and inhibit proliferation of GBM cell lines suggesting an anticancer effect of these miRNAs. miR-320 is also located at 8p; its altered expression in human cholangiocarcinoma cell lines may contri- bute to cholangiocyte-specific responses to chemo- therapy.410 In patients with cytogenetically normal acute myeloid leukemia, Marcucci et al.411 found an altered expression of 12 miRNAs (including miR-124a and miR-320) that was associated with clinical outcome in a subgroup of patients with high-risk acute myeloid leukemia. Interestingly, the methyl- CpG-binding domain (MBD) proteins (MBD1, MBD2, MBD3, MBD4 and MeCP2) are critical mediators of DNA methylation-regulated epigenetic processes. The MBD family proteins are associated with tumorigenesis and drug resistance. Mutations in MBD2 and MeCP2 genes are likewise implicated in a number of related but distinct postnatal neurodevelopmental disorders, including X-linked mental retardation disorders, autism and Rett syndrome,412–415 and are putative targets for miR- 124a and miR-320 predicted by computational analysis.416 Thus, miRNAs may provide a homeo- static mechanism for maintaining MBD2 and MeCP2 levels. It is noted that using this database of predicted miRNA target genes, we have identified new putative targets for miR-124a (FMR1 or fragile X-linked mental retardation) and miR-320 (NLGN3 or neuroligin3; AUTS2 or autism susceptibility candidate 2; A2BP1 or ataxin 2-binding protein 1, also called FOX1), which are associated with autism, schizophrenia and related syndromes.417 The function of some of these genes is presently unknown (AUTS2). Others are important in glutamatergic synapse function and/or in neuronal cell adhesion (FMR1 and NLGN3), neuronal activity regulation (FMR1 and A2BP1) and in endosomal trafficking (A2BP1).
miRNAs expression is the subject of considerable interest in schizophrenia.418–423 Very little is known about the role of miRNAs in autism; however, current findings suggest that alterations in the interactions between miRNAs and their mRNA targets may contribute to autism phenotypic variation.424–426 For
instance, Abu-Elneel et al.426 found that miRNA-320 (at 8p21.3) and miRNA-598 (at 8p23.1) are dysregu- lated in postmortem cerebellar cortex from 13 indi- viduals with autism spectrum disorders compared with nonautism controls.
Conclusions and future directions
Although many questions remain unanswered,427 the research should focus on common or related path- ways, or processes that potentially represent a point of convergence for molecular signaling not only among schizophrenia, autism or other neuropsychia- tric disorders, but also with cancer. Compared with classical approaches, focusing on a group of genes belonging to the same functional pathway or that operates together as a network could yield the best results. The cross-sectional dimension raises the possibility that shared components of the schizo- phrenia/cancer phenotype, or other common human diseases, might be used to distinguish genetic and molecular pathways in these severe disorders. Con- sistent with this idea, analysis of the genes within chromosome 8p represents a rich resource to under- stand the biological connections among disorders that are considered to be distinct.
Acknowledgments
This study was supported by grants from the follow- ing: Spanish FIS-MSC Grant PI051293, the Spanish Ministry of Health, Instituto de Salud Carlos III, CIBERSAM and Fundacio ́n Alicia Koplowitz to RTS; and from Nina Ireland and NIMH R37MH49428-16 to JLRR. We thank Teresa Esca ́ mez, Juan Antonio Martı ́nez-Gime ́nez, Vicent Balanza ́-Martı ́nez, Salva- dor Martı ́nez, Eduard Vieta and Manuel Go ́ mez- Beneyto for their helpful advice on previous versions of the manuscript and for their excellent technical assistance.
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