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Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis

Smoller, Jordan W., Kendler, Kenneth, Craddock, Nicholas John ORCID:, Lee, Phil Hyoun, Neale, Benjamin M., Nurnberger, John I., Ripke, Stephan, Santangelo, Susan, Sullivan, Patrick F., Purcell, Shaun, Anney, Richard ORCID:, Buitelaar, Jan, Fanous, Ayman, Faraone,, Stephen V., Hoogendijk, Witte, Lesch, Klaus-Peter, Levinson, Douglas F., Perlis, Roy H., Rietschel, Marcella, Riley, Brien, Sonuga-Barke, Edmund, Schachar, Russell, Schulze, Thomas G., Thapar, Anita ORCID:, Neale, Michael, Bender, Patrick, Cichon, Sven, Daly, Mark J., Kelsoe, John, Lehner, Thomas, O'Donovan, Michael Conlon ORCID:, Gejman, Pablo, Sebat, Jonathan and Sklar, Pamela 2013. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet 381 (9875) , pp. 1371-1379. 10.1016/S0140-6736(12)62129-1

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Background: Findings 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. Methods: 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. Findings: 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. Interpretation: 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information: Authors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium
Publisher: Elsevier
ISSN: 0140-6736
Funders: National Institute of Mental Health
Last Modified: 10 Nov 2022 12:41

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