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Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.

ABSTRACT: BACKGROUND:Genome-wide association studies have been extensively applied in identifying SNP associated with major psychiatric disorders. However, the SNPs identified by the prevailing univariate approach only explain a small percentage of the genetic variance of traits, and the extensive data have shown the major psychiatric disorders have common biological mechanisms and the overlapping pathophysiological pathways. METHODS:We applied the genetic pleiotropy-informed metaCCA method on summary statistics data from the Psychiatric Genomics Consortium Cross-Disorder Group to examine the overlapping genetic relations between the five major psychiatric disorders. Furthermore, to refine all genes, we performed gene-based association analyses for the five disorders respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes. RESULTS:After metaCCA analysis, 1147 SNPs reached the Bonferroni corrected threshold (p?

SUBMITTER: Jia X

PROVIDER: S-EPMC6343670 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.

Jia XiaoCan X Yang YongLi Y Chen YuanCheng Y Cheng ZhiWei Z Du Yuhui Y Xia Zhenhua Z Zhang Weiping W Xu Chao C Zhang Qiang Q Xia Xin X Deng HongWen H Shi XueZhong X

Journal of affective disorders 20180717

<h4>Background</h4>Genome-wide association studies have been extensively applied in identifying SNP associated with major psychiatric disorders. However, the SNPs identified by the prevailing univariate approach only explain a small percentage of the genetic variance of traits, and the extensive data have shown the major psychiatric disorders have common biological mechanisms and the overlapping pathophysiological pathways.<h4>Methods</h4>We applied the genetic pleiotropy-informed metaCCA method ...[more]

PMID: 30212762

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Project description:BackgroundFindings from family and twin studies suggest that genetic contributions to psychiatric disorders do not in all cases map to present diagnostic categories. We aimed to identify specific variants underlying genetic effects shared between the five disorders in the Psychiatric Genomics Consortium: autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.MethodsWe analysed genome-wide single-nucleotide polymorphism (SNP) data for the five disorders in 33,332 cases and 27,888 controls of European ancestory. To characterise allelic effects on each disorder, we applied a multinomial logistic regression procedure with model selection to identify the best-fitting model of relations between genotype and phenotype. We examined cross-disorder effects of genome-wide significant loci previously identified for bipolar disorder and schizophrenia, and used polygenic risk-score analysis to examine such effects from a broader set of common variants. We undertook pathway analyses to establish the biological associations underlying genetic overlap for the five disorders. We used enrichment analysis of expression quantitative trait loci (eQTL) data to assess whether SNPs with cross-disorder association were enriched for regulatory SNPs in post-mortem brain-tissue samples.FindingsSNPs at four loci surpassed the cutoff for genome-wide significance (p<5×10(-8)) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.InterpretationOur findings show that specific SNPs are associated with a range of psychiatric disorders of childhood onset or adult onset. In particular, variation in calcium-channel activity genes seems to have pleiotropic effects on psychopathology. These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause.FundingNational Institute of Mental Health.

Dataset Information

Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.

Publications

Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.

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