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 language | English (US) |
|---|---|
| Pages (from-to) | 1371-1379 |
| Number of pages | 9 |
| Journal | The Lancet |
| Volume | 381 |
| Issue number | 9875 |
| DOIs | |
| State | Published - Apr 1 2013 |
ASJC Scopus subject areas
- General Medicine
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In: The Lancet, Vol. 381, No. 9875, 01.04.2013, p. 1371-1379.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Identification of risk loci with shared effects on five major psychiatric disorders
T2 - A genome-wide analysis
AU - Cross-Disorder Group of the Psychiatric Genomics Consortium
AU - Smoller, Jordan W.
AU - Kendler, Kenneth K.
AU - Craddock, Nicholas
AU - Lee, Phil Hyoun
AU - Neale, Benjamin M.
AU - Nurnberger, John N.
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 G.
AU - Thapar, Anita
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 - Devlin, Bernie
AU - Sullivan, Patrick
AU - O'Donovan, Michael
N1 - Funding Information: This study is the largest genome-wide analysis of psychiatric illness so far and the first to provide evidence that specific SNPs are significantly associated with a range of childhood-onset and adult-onset psychiatric disorders. For the five disorders studied, SNPs at four loci—regions on chromosomes 3p21 and 10q24, and SNPs in two L-type voltage-gated calcium-channel subunits, CACNA1C and CACNB2 —exceeded the cutoff for genome-wide significance in the primary analysis. The strongest signal was within a region on chromosome 3p21.1. Aggregate polygenic risk scores for a broad set of common variants showed cross-disorder effects for all the adult-onset disorders (bipolar and major depressive disorder, and schizophrenia) and nominally between autism spectrum disorders and both bipolar disorder and schizophrenia. In view of extensive linkage disequilibrium in the 3p21.1 region, encompassing more than 30 genes, we could not identify the causal locus. Genome-wide significant association to the 3p21.1 region has previously been reported in GWAS of samples overlapping with ours at rs1042779 (12 kb from our peak SNP) for bipolar disorder, 28 rs736408 (2 kb) for a combined bipolar disorder and schizophrenia phenotype, 7 and rs2251219 (248 kb) for a combined major depressive and bipolar disorder phenotype. 29 Reanalysis of this last combined dataset suggested that the signal was largely attributable to the group with bipolar disorder. 30 Furthermore, the association evidence for our peak chromosome 3 SNP rs2535629 was genome-wide significant in a joint analysis of bipolar disorder and schizophrenia samples done by the PGC schizophrenia group (p=7·8×10 −9 ). 6 Our model-selection analysis was designed to characterise the range of phenotypic effects for loci that showed significant association; however, the statistical evidence and effect size for each contributing disorder can vary. Although the best-fit model for the chromosome 3p21 region included all five disorders, interpretation of these results is complicated by evidence from a PGC GWAS mega-analysis of major depressive disorder. 17 In the discovery phase of that analysis, which consisted of 9240 major depressive disorder cases and 9519 controls many of whom overlap with samples reported here, the smallest association p value for this region (rs2535629) was 0·00013. However, no association was noted in a replication dataset of 6783 cases and 50 695 controls (p=0·70) for that disorder, and the combined discovery and replication phase p value was 0·0031. Thus, any association between this region and major depressive disorder is unclear. Two of the four genome-wide significant signals in our analysis localise to introns of brain-expressed genes encoding L-type voltage-gated calcium-channel subunits ( CACNA1C and CACNB2 ). Previous disorder-specific GWAS, overlapping with the samples included here, identified CACNA1C as a susceptibility gene for bipolar disorder, 7,31 schizophrenia, 6,17 and major depressive disorder. 32 Gain-of-function mutations in CACNA1C cause Timothy syndrome, a developmental disorder in which the phenotypic range includes autism . 33 Consistent with a pleiotropic role , neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, 34 executive function, 34 attention, 35 and memory. 36 CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S ) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signalling proteins and molecules. 37 Although previous PGC analyses (schizophrenia and bipolar disorder) did not identify CACNB2 as a risk gene, a variant in CACNB2 (52 kb from our peak SNP) was one of the main signals in an independent GWAS of bipolar disorder in Han Chinese individuals. 19 The pleiotropic effects of voltage-gated calcium channels on childhood-onset and adult-onset psychiatric disorders are underscored by pathway analysis in which calcium-channel activity genes, including our main two L-type subunit genes, showed significant enrichment in the five disorder dataset. The PGC analysis of bipolar disorder reported enrichment of a pathway including CACNA1C and CACNA1D ; importantly, however, we detected enrichment of these genes after exclusion of the bipolar disorder dataset. Thus, our results suggest that voltage-gated calcium signalling, and, more broadly, calcium-channel activity, could be an important biological process in psychiatric disorders. A fourth region associated with cross-disorder effects was on chromosome 10, encompassing several genes with the peak signal in an intron of AS3MT . Loci previously associated with schizophrenia and bipolar disorder 6,7 had varying evidence of association for the other major psychiatric disorders. For example, a locus previously strongly associated with schizophrenia, encompassing MIR137 and DPYD on chromosome 1, showed similar evidence of association with autism spectrum disorders; this finding is consistent with reports that autism spectrum disorders are related to microdeletions of this region. 38,39 Accumulating evidence, including that from clinical, epidemiological, and molecular genetic studies, suggests that some genetic risk factors are shared between neuropsychiatric disorders. Genome-wide studies have identified rare copy-number variants that confer risk of several neuropsychiatric disorders including autism, attention deficit-hyperactivity disorder, epilepsy, intellectual disability, and schizophrenia. 39 Our analyses of 14 SNPs previously identified as being genome-wide significantly associated with schizophrenia and bipolar disorder suggest that some loci identified in studies of individual disorders have broader phenotypic effects. Our results suggest a diversity of findings, with some SNPs showing diagnostic specificity and others pleiotropic effects on two or more of the five disorders. These results should be interpreted in consideration of several limitations. First, we compared models of cross-disorder effects on the basis of the most often used goodness-of-fit measures, but other criteria might yield different results. For all four of the risk loci identified in the primary meta-analysis, the selected model had a substantially better fit than any alternative models had. However, for some loci that did not reach genome-wide significance, the difference in fit between our best-fitting and alternative models was moderate ( appendix pp 38–45 ), so more than one model could be consistent with the noted effects. Second, diagnostic misclassification (eg, reciprocal misdiagnosis of cases of schizophrenia and bipolar disorder) could produce spurious evidence of genetic overlap between disorders. 40 However,a substantial degree of misdiagnosis would be needed to account for our findings of loci that affect all or subsets of five disorders whose diagnostic criteria are fairly distinct. Third, the five disorders we examined were limited to those for which large-scale GWAS datasets have been assembled by the PGC and processed through a uniform quality-control process. As further datasets become available, more comprehensive analyses of cross-disorder genetic effects on psychiatric illness should be pursued. Fourth, we restricted our analyses to individuals of European ancestry. Whether our findings apply to other populations is unknown. Finally, GWAS designs are suited to identify common variant aspects of genetic architecture; further studies (including analyses of copy-number variants and rare mutations) will be needed to account more completely for shared genetic contributions across disorders. As in almost all GWAS of complex disorders reported so far, the effect sizes of genome-wide significant loci are individually quite small and the variance they account for is insufficient for predictive or diagnostic usefulness by themselves. However, our study is the first large-scale effort to characterise allelic effects across five psychiatric disorders, incorporating single locus, multilocus, and pathway analyses. The identification of genetic variants that confer risk of a diverse set of psychiatric disorders parallels findings from other medical specialties. Most notably, GWAS ). In particular, alterations in calcium-channel signalling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology. 41,42 of autoimmune disorders have shown extensive overlap in genetic variants that affect a diverse range of diseases, including rheumatoid arthritis, coeliac disease, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, and type 1 diabetes. Our results provide insights into the shared causation of psychiatric disorders ( panel This online publication has been corrected. The corrected version first appeared at thelancet.com on April 19, 2013 Correspondence to: Dr Jordan W Smoller, Simches Research Building, Massachusetts General Hospital, Boston, MA 02114, USA [email protected] Contributors Overall coordination : Jordan W Smoller, Kenneth Kendler, Nicholas Craddock. Writing committee : Jordan W Smoller (lead), Nicholas Craddock, Kenneth Kendler, Phil Hyoun Lee, Benjamin M Neale, John I Nurnberger, Stephan Ripke, Susan Santangelo, Patrick F Sullivan. Statistical analysis: Stephan Ripke (lead), Kenneth Kendler, Phil Hyoun Lee, Benjamin M Neale, Shaun Purcell. Editorial revisions: Richard Anney, Jan Buitelaar, Ayman Fanous, Stephen V Faraone, Witte Hoogendijk, Klaus-Peter Lesch, Douglas F Levinson, Roy H Perlis, Shaun Purcell, Marcella Rietschel, Brien Riley, Edmund Sonuga-Barke, Russell Schachar, Thomas G Schulze, Anita Thapar. PGC Cross-Disorder Group : Nicholas Craddock, Kenneth S Kendler, Jordan W Smoller (cochairs), Ayman Fanous, Benjamin Neale, Michael Neale, John I Nurnberger, Roy Perlis, Shaun Purcell, Marcella Rietschel, Susan Santangelo, Thomas G Schulze, Anita Thapar. PGC coordinating committee : Patrick F Sullivan (chair), Patrick Bender, Sven Cichon, Nicholas Craddock, Mark J Daly, Stephen V Faraone, John Kelsoe, Thomas Lehner, Douglas Levinson, Mick O'Donovan, Pablo Gejman, Jonathan Sebat, Pamela Sklar, Jordan W Smoller. See appendix for PGC Collaborators from Analysis Committee (Mark J Daly, chair), ADHD Workgroup (Stephen V Faraone, chair ), Autism Workgroup (Mark Daly, Bernie Devlin, cochairs), Bipolar Disorder Workgroup (John Kelsoe, Pamela Sklar, cochairs), Major Depressive Disorder Workgroup (Patrick Sullivan, chair), Schizophrenia Workgroup (Michael O'Donovan, chair). Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank the study participants, and the research staff at the many study sites. This work was supported by NIMH grant U01 MH085520. Numerous grants from the National Institutes of Health (USA), and similar numbers of government grants from other countries, and substantial private and foundation support enabled this work.
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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UR - http://www.scopus.com/inward/citedby.url?scp=84876296688&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(12)62129-1
DO - 10.1016/S0140-6736(12)62129-1
M3 - Article
C2 - 23453885
AN - SCOPUS:84876296688
SN - 0140-6736
VL - 381
SP - 1371
EP - 1379
JO - The Lancet
JF - The Lancet
IS - 9875
ER -