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A comprehensive family-based replication study of schizophrenia genes.

ABSTRACT: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.To identify SCZ susceptibility genes.We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.Case-control status for SCZ.Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets.

SUBMITTER: Aberg KA

PROVIDER: S-EPMC5297889 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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A comprehensive family-based replication study of schizophrenia genes.

Aberg Karolina A KA Liu Youfang Y Bukszár Jozsef J McClay Joseph L JL Khachane Amit N AN Andreassen Ole A OA Blackwood Douglas D Corvin Aiden A Djurovic Srdjan S Gurling Hugh H Ophoff Roel R Pato Carlos N CN Pato Michele T MT Riley Brien B Webb Todd T Kendler Kenneth K O'Donovan Mick M Craddock Nick N Kirov George G Owen Mike M Rujescu Dan D St Clair David D Werge Thomas T Hultman Christina M CM Delisi Lynn E LE Sullivan Patrick P van den Oord Edwin J EJ

JAMA psychiatry 20130601 6

<h4>Importance</h4>Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.<h4>Objective</h4>To identify SCZ susceptibility genes.<h4>Design</h4>We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases tha ...[more]

PMID: 23894747

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Project description:Suicidal behavior (SB) has a complex etiology involving genes and environment. One of the genetic components in SB could be copy number variations (CNVs), as CNVs are implicated in neurodevelopmental disorders. However, a recently published genome-wide and case-control study did not observe any significant role of CNVs in SB. Here we complemented these initial observations by instead using a family-based trio-sample that is robust to control biases, having severe suicide attempt (SA) in offspring as main outcome (n = 660 trios). We first tested for CNV associations on the genome-wide Illumina 1M SNP-array by using FBAT-CNV methodology, which allows for evaluating CNVs without reliance on CNV calling algorithms, analogous to a common SNP-based GWAS. We observed association of certain T-cell receptor markers, but this likely reflected inter-individual variation in somatic rearrangements rather than association with SA outcome. Next, we used the PennCNV software to call 385 putative rare (<1%) and large (>100 kb) CNVs, observed in n = 225 SA offspring. Nine SA offspring had rare CNV calls in a set of previously schizophrenia-associated loci, indicating the importance of such CNVs in certain SA subjects. Several additional, very large (>1MB) sized CNV calls in 15 other SA offspring also spanned pathogenic regions or other neural genes of interest. Overall, 45 SA had CNVs enriched for 65 medically relevant genes previously shown to be affected by CNVs, which were characterized by a neurodevelopmental biology. A neurodevelopmental implication was partly congruent with our previous SNP-based GWAS, but follow-up analysis here indicated that carriers of rare CNVs had a decreased burden of common SNP risk-alleles compared to non-carriers. In conclusion, while CNVs did not show genome-wide association by the FBAT-CNV methodology, our preliminary observations indicate rare pathogenic CNVs affecting neurodevelopmental functions in a subset of SA, who were distinct from SA having increased SNP risk-allele burden. These observations may open up new avenues in the genetic etiology of SB.

Dataset Information

A comprehensive family-based replication study of schizophrenia genes.

Publications

A comprehensive family-based replication study of schizophrenia genes.

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