Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

Universität Regensburg, Ratisbon, Bavaria, Germany
American Journal of Psychiatry (Impact Factor: 12.3). 08/2012; 169(9):963-973. DOI: 10.1176/appi.ajp.2012.11091423
Source: PubMed


The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs).

The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs.

No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10(-17), explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families.

Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

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Available from: Ami Citri, Nov 21, 2015
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    • "CNVs in COS vs healthy siblings and vs adult onset SCZ and did not therefore represent a straight forward case control study design. Likewise the study Levinson et al. (2012) was also excluded because their study was not a case control study, and the Grozeva et al. (2010) study was excluded because they had focused their analysis on a healthy control group compared with historical results in patients with SCZ. In our pre-quality control meta-analysis, we utilized a fixed effect (M-H) method and found a pooled OR "
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    ABSTRACT: Background: In the last 5 years an increasing number of studies have found that individuals who have micro-duplications at 16p11.2 may have an increased risk of mental disorders including psychotic syndromes. Objective: Our main aim was to review all the evidence in the literature for the association between copy number variants (CNVs) at 16p11.2 and psychosis. Methods: We have conducted a systematic review and a meta-analysis utilising the PRISMA statement criteria. We included all original studies (published in English) which presented data on CNVs at 16p11.2 in patients affected by schizophrenia, schizoaffective disorder or bipolar disorder. Results: We retrieved 15 articles which fulfilled our inclusion criteria. Eleven articles were subsequently selected for a meta-analysis that showed a 10 fold increased risk of psychosis in patients with proximal 16p11.2 duplications. We conducted a second meta-analysis of those studies with low risk of overlap in order to obtain the largest possible sample with the lowest risk of repeated results: 5 studies were selected and we found an odds ratio (OR) of 14.4 (CI=5.2-39.8; p<0.001) for psychosis with proximal 16p11.2 duplications. The results were not significant for micro-deletions in the same region. Finally extracting only those studies that included patients with schizophrenia we found an OR=16.0 (CI=5.4-47.3: p<0.001) CONCLUSIONS: There is a fourteen fold-increased risk of psychosis and a sixteen fold increased risk of schizophrenia in individuals with micro-duplication at proximal 16p11.2.
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    • "Here, we focus on the molecular evolution of protein-coding genes associated with schizophrenia, autism, and other neuropsychiatric diseases compared across mammalian species and among disease classes, with a focus on the primate (chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, and squirrel monkey) and human lineages. Recent genome wide association studies (GWAS) have identified multiple genomic loci associated with autism (Ma et al., 2009; Wang et al., 2009; Weiss et al., 2009; Anney et al., 2010, 2012; Tsang et al., 2013) and Asperger syndrome (Salyakina et al., 2010), and schizophrenia (Fanous et al., 2012; Levinson et al., 2012; Aberg et al., 2013; Ripke et al., 2013). Using these datasets and similar meta-analyses in the literature that have identified genes implicated in neuropsychiatric disease it is possible to test whether mutations have occurred recently and uniquely in the evolution of humans, or whether similar changes are seen in other mammals. "
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    ABSTRACT: Many psychiatric diseases observed in humans have tenuous or absent analogs in other species. Most notable among these are schizophrenia and autism. One hypothesis has posited that these diseases have arisen as a consequence of human brain evolution, for example, that the same processes that led to advances in cognition, language, and executive function also resulted in novel diseases in humans when dysfunctional. Here, the molecular evolution of the protein-coding regions of genes associated with these and other psychiatric disorders are compared among species. Genes associated with psychiatric disorders are drawn from the literature and orthologous sequences are collected from eleven primate species (human, chimpanzee, bonobo, gorilla, orangutan, gibbon, macaque, baboon, marmoset, squirrel monkey, and galago) and 34 non-primate mammalian species. Evolutionary parameters, including dN/dS, are calculated for each gene and compared between disease classes and among species, focusing on humans and primates compared to other mammals, and on large-brained taxa (cetaceans, rhinoceros, walrus, bear, and elephant) compared to their small-brained sister species. Evidence of differential selection in humans to the exclusion of non-human primates was absent, however elevated dN/dS was detected in catarrhines as a whole, as well as in cetaceans, possibly as part of a more general trend. Although this may suggest that protein changes associated with schizophrenia and autism are not a cost of the higher brain function found in humans, it may also point to insufficiencies in the study of these diseases including incomplete or inaccurate gene association lists and/or a greater role of regulatory changes or copy number variation. Through this work a better understanding of the molecular evolution of the human brain, the pathophysiology of disease, and the genetic basis of human psychiatric disease is gained.
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    • "The molecular elements other than LCRs favoring CNV formation are poorly understood, and therefore, a good starting point would be to study regions prone to a relatively high CNV frequency, like the NRXN1 locus previously associated with schizophrenia [Kirov et al., 2008; Walsh et al., 2008; Rujescu et al., 2009; Levinson et al., 2012], autism [Kim et al., 2008; Marshall et al., 2008; Bucan et al., 2009; Glessner et al., 2009; Wis´niowiecka-Kowalnik et al., 2010], and epilepsy [Møller et al., 2013]. The high frequency of deletions found in the NRXN1 locus raises the possibility that genomic instability events in this region are commonly driven by a single mechanism. "
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    ABSTRACT: Genome instability plays fundamental roles in human evolution and phenotypic variation within our population. This instability leads to genomic rearrangements that are involved in a wide variety of human disorders, including congenital and neurodevelopmental disorders, and cancers. Insight into the molecular mechanisms governing such genomic rearrangements may increase our understanding of disease pathology and evolutionary processes. Here we analyse 17 carriers of non-recurrent deletions in the NRXN1 gene, which have been associated with neurodevelopmental disorders, e.g. schizophrenia, autism and epilepsies. 17 non-recurrent NRXN1 deletions identified by GWA were sequenced to map the breakpoints of each. Meme … etc. was used to identify shared patterns between the deletions and compare these were previously studies on non-recurrent deletions. We discovered two novel sequence motifs shared between all 17 NRXN1 deletions and a significantly higher AT nucleotide content at the breakpoints, compared to the overall nucleotide content on chromosome 2. We found different alteration of sequence at the breakpoint; small insertions and duplications giving rise to short microhomology sequences. No single mechanism seems to be implicated in the deletion events, but the results suggest that NHEJ, FoSTeS or MMBIR is implicated. The two novel sequence motifs together with a high AT content in all in NRXN1 deletions may lead to increased instability leading to a increase susceptibility to a single stranded structures. This favours potentially repaired by NHEJ mechanism of double strand breaks or may leading to replication errors. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(1):52-61. DOI:10.1002/ajmg.b.32204 · 3.42 Impact Factor
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