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

Smoller, Jordan W., Craddock, Nicholas, Kendler, Kenneth, Lee, Phil Hyoun, Neale, Benjamin M., Nurnberger, John I., Ripke, Stephan, Santangelo, Susan, Sullivan, Patrick F., Cross-Disorder Group of the Psychiatric Genomics Consortium and Middeldorp, Christel (2013) Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. The Lancet, 381 9875: 1371-1379. doi:10.1016/S0140-6736(12)62129-1

Author Smoller, Jordan W.
Craddock, Nicholas
Kendler, Kenneth
Lee, Phil Hyoun
Neale, Benjamin M.
Nurnberger, John I.
Ripke, Stephan
Santangelo, Susan
Sullivan, Patrick F.
Cross-Disorder Group of the Psychiatric Genomics Consortium
Middeldorp, Christel
Title Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Journal name The Lancet   Check publisher's open access policy
ISSN 0140-6736
Publication date 2013-04-01
Sub-type Article (original research)
DOI 10.1016/S0140-6736(12)62129-1
Open Access Status Not yet assessed
Volume 381
Issue 9875
Start page 1371
End page 1379
Total pages 9
Place of publication London, United Kingdom
Publisher The Lancet Publishing Group
Language eng
Formatted abstract

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.


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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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