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

Cross-Disorder Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticle

1524 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1371-1379
Number of pages9
JournalThe Lancet
Volume381
Issue number9875
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

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Single Nucleotide Polymorphism
Psychiatry
Genome
Calcium Channels
Bipolar Disorder
Schizophrenia
Quantitative Trait Loci
Twin Studies
Calcium Signaling
Major Depressive Disorder
Brain
Attention Deficit Disorder with Hyperactivity
Genomics
Psychopathology
Genes
Chromosomes
Logistic Models
Genotype
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Identification of risk loci with shared effects on five major psychiatric disorders : A genome-wide analysis. / Cross-Disorder Group of the Psychiatric Genomics Consortium.

In: The Lancet, Vol. 381, No. 9875, 01.04.2013, p. 1371-1379.

Research output: Contribution to journalArticle

Cross-Disorder Group of the Psychiatric Genomics Consortium. / Identification of risk loci with shared effects on five major psychiatric disorders : A genome-wide analysis. In: The Lancet. 2013 ; Vol. 381, No. 9875. pp. 1371-1379.
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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.",
author = "{Cross-Disorder Group of the Psychiatric Genomics Consortium} and Smoller, {Jordan W.} and Kenneth Kendler and Nicholas Craddock and Lee, {Phil Hyoun} and Neale, {Benjamin M.} and John Nurnberger and Stephan Ripke and Susan Santangelo and Sullivan, {Patrick S.} and Neale, {Benjamin N.} and Shaun Purcell and Richard Anney and Jan Buitelaar and Ayman Fanous and Faraone, {Stephen F.} and Witte Hoogendijk and Lesch, {Klaus Peter} and Levinson, {Douglas L.} and Perlis, {Roy P.} and Marcella Rietschel and Brien Riley and Edmund Sonuga-Barke and Russell Schachar and Schulze, {Thomas S.} and Anita Thapar and Kendler, {Kenneth K.} and Smoller, {Jordan S.} and Michael Neale and Roy Perlis and Patrick Bender and Sven Cichon and Daly, {Mark D.} and John Kelsoe and Thomas Lehner and Douglas Levinson and Mick O'Donovan and Pablo Gejman and Jonathan Sebat and Pamela Sklar and Mark Daly and Bernie Devlin and Patrick Sullivan and Michael O'Donovan",
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T2 - A genome-wide analysis

AU - Cross-Disorder Group of the Psychiatric Genomics Consortium

AU - Smoller, Jordan W.

AU - Kendler, Kenneth

AU - Craddock, Nicholas

AU - Lee, Phil Hyoun

AU - Neale, Benjamin M.

AU - Nurnberger, John

AU - Ripke, Stephan

AU - Santangelo, Susan

AU - Sullivan, Patrick S.

AU - Neale, Benjamin N.

AU - Purcell, Shaun

AU - Anney, Richard

AU - Buitelaar, Jan

AU - Fanous, Ayman

AU - Faraone, Stephen F.

AU - Hoogendijk, Witte

AU - Lesch, Klaus Peter

AU - Levinson, Douglas L.

AU - Perlis, Roy P.

AU - Rietschel, Marcella

AU - Riley, Brien

AU - Sonuga-Barke, Edmund

AU - Schachar, Russell

AU - Schulze, Thomas S.

AU - Thapar, Anita

AU - Kendler, Kenneth K.

AU - Smoller, Jordan S.

AU - Neale, Michael

AU - Perlis, Roy

AU - Bender, Patrick

AU - Cichon, Sven

AU - Daly, Mark D.

AU - Kelsoe, John

AU - Lehner, Thomas

AU - Levinson, Douglas

AU - O'Donovan, Mick

AU - Gejman, Pablo

AU - Sebat, Jonathan

AU - Sklar, Pamela

AU - Daly, Mark

AU - Devlin, Bernie

AU - Sullivan, Patrick

AU - O'Donovan, Michael

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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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