Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
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Psychiatric Genomics Consortium
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CitationLancet 2013, 381 (9875):1371-9
AbstractFindings 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.
We 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.
SNPs 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.
Our 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.
National Institute of Mental Health.
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- Risk loci with shared effects on major psychiatric disorders.
- Authors: Levine J
- Issue date: 2013 Jul 27
- Shared genetics among major psychiatric disorders.
- Authors: Serretti A, Fabbri C
- Issue date: 2013 Apr 20
- Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.
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- Issue date: 2013 Sep
- Multivariate analysis of genome-wide data to identify potential pleiotropic genes for five major psychiatric disorders using MetaCCA.
- Authors: Jia X, Yang Y, Chen Y, Cheng Z, Du Y, Xia Z, Zhang W, Xu C, Zhang Q, Xia X, Deng H, Shi X
- Issue date: 2019 Jan 1
- Genome-wide Association for Major Depression Through Age at Onset Stratification: Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.
- Authors: Power RA, Tansey KE, Buttenschøn HN, Cohen-Woods S, Bigdeli T, Hall LS, Kutalik Z, Lee SH, Ripke S, Steinberg S, Teumer A, Viktorin A, Wray NR, Arolt V, Baune BT, Boomsma DI, Børglum AD, Byrne EM, Castelao E, Craddock N, Craig IW, Dannlowski U, Deary IJ, Degenhardt F, Forstner AJ, Gordon SD, Grabe HJ, Grove J, Hamilton SP, Hayward C, Heath AC, Hocking LJ, Homuth G, Hottenga JJ, Kloiber S, Krogh J, Landén M, Lang M, Levinson DF, Lichtenstein P, Lucae S, MacIntyre DJ, Madden P, Magnusson PKE, Martin NG, McIntosh AM, Middeldorp CM, Milaneschi Y, Montgomery GW, Mors O, Müller-Myhsok B, Nyholt DR, Oskarsson H, Owen MJ, Padmanabhan S, Penninx BWJH, Pergadia ML, Porteous DJ, Potash JB, Preisig M, Rivera M, Shi J, Shyn SI, Sigurdsson E, Smit JH, Smith BH, Stefansson H, Stefansson K, Strohmaier J, Sullivan PF, Thomson P, Thorgeirsson TE, Van der Auwera S, Weissman MM, CONVERGE Consortium, CARDIoGRAM Consortium, GERAD1 Consortium., Breen G, Lewis CM
- Issue date: 2017 Feb 15