Study Report

Reference	Cross-Disorder Group of the Psychiatric Genomics Consortium,2013 PMID: 23453885
Citation	Cross-Disorder Group of the Psychiatric Genomics Consortium,(2013). "Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis." Lancet.
Disease Type	Bipolar Disorder & Schizophrenia & Major depressive disorder
Study Design	case-control
Study Type	Genome-wide association study
Sample Size	The final dataset consisted of 33 332 cases and 27 888 controls(including pseudocontrols formed from nontransmitted alleles) distributed among the five disorder groups: autism spectrum disorders (4788 trio cases, 4788 trio pseudocontrols, 161 cases, 526 controls), attention defi cit-hyperactivity disorder (1947 trio cases, 1947 trio pseudocontrols, 840 cases, 688 controls), bipolar disorder (6990 cases, 4820 controls), major depressive disorder (9227 cases, 7383 controls), and schizophrenia (9379 cases, 7736 controls).
SNP/Region/Marker Size	1 250 922 SNPs
Predominant Ethnicity	Caucasian
Population	European

Sample Diagnosis	DSM-IV
Sample Status	The sample for these analyses consisted of cases, controls, and family-based samples assembled for previous genome-wide PGC mega-analyses of individuallevel data.Cases and controls were not related. For the family-based samples, we matched alleles transmitted to aff ected off spring (trio cases) with untransmitted alleles (pseudo controls). We estimated the identity-bydescent relation for all pairs of individuals to identify any duplicate individuals in the component datasets. When duplicates were detected, one member of each set was retained. We then randomly allocated these individuals, with a random number generator, to a disorder casecontrol dataset. Sample sizes diff er from previous reports because of this allocation of overlapping individuals. All patients were of European ancestory and met criteria from the DSM third edition revised or fourth edition for the primary disorder of interest.
Technique	Genotyping
Statistical Method	In the primary analysis, we combined eff ects of each disease analysis by a meta-analytic approach that applied a weighted Z-score,18 in which weights equalled the inverse of the regression coefficient's standard error. This strategy assumed a fixed-effects model, with weights indicating the sample size of the disease-specific studies. In a second analytical approach, we did a five-degree-of freedom test by summing the values for each individual disease meta-analysis.
Result Summary	SNPs at four loci surpassed the cutoff for genome-wide significance (p<5x10-8) 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.