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

Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
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.
0140-6736
1371-1379
Sonuga-Barke, Edmund J.S.
bc80bf95-6cf9-4c76-a09d-eaaf0b717635
Sonuga-Barke, Edmund J.S.
bc80bf95-6cf9-4c76-a09d-eaaf0b717635

Sonuga-Barke, Edmund J.S. (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).

Record type: Article

Abstract

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.

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More information

Published date: 2013
Organisations: Clinical Neuroscience

Identifiers

Local EPrints ID: 363342
URI: https://eprints.soton.ac.uk/id/eprint/363342
ISSN: 0140-6736
PURE UUID: 443b040f-9674-4780-a6c2-c8eaa88d2f22

Catalogue record

Date deposited: 24 Mar 2014 14:54
Last modified: 05 Oct 2018 12:09

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Contributors

Author: Edmund J.S. Sonuga-Barke

University divisions

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