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

By Jordan W. Smoller, Kenneth S. Kendler, N. Craddock, Phil H. Lee, Benjamin M. Neale, J. Nurnberger, S. Ripke, Susan L. Santangelo, P. Sullivan, S. Purcell and 24 more. The Lancet, 2013

2,591 citations recorded by the source corpus.

Summary 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. Funding National Institute of Mental Health.

Subfields: Genetics, Molecular Biology, Psychiatry and Mental health

View Paper: https://www.semanticscholar.org/paper/927156050101c0d53bc0b6f2e52f153638d56a0b

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Citations in the corpus

The p Factor: One General Psychopathology Factor in the Structure of Psychiatric Disorders? (2014, result): “A recent genome-wide association study that indicated that genetic variants are linked to multiple diagnoses is consistent with this hypothesis (Smoller et al., 2013).”
Sensitivity and Specificity of Information Criteria (2018, neutral): “The ICs can still be practically useful in this setting (e.g., Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013).”
The Structure of Psychopathology in Adolescence (2015, background): “This would explain why the genes involved in the etiology of psychopathology seem to operate in a pleiotropic fashion, enhancing risk for any and all disorders rather than breeding true to any single disorder (Smoller, 2013).”