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

Summary 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 Genomi... Full description

Journal Title: The Lancet (British edition) 2013, Vol.381 (9875), p.1371-1379
Main Author: Smoller, J.W
Other Authors: Craddock, N , Kendler, K , Lee, P.H , Neale, B.M , Nurnberger, J.I , Ripke, S , Santangelo, S , Sullivan, P.F , Buitelaar, J.K , Franke, B , et al
Format: Electronic Article Electronic Article
Language: English
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Quelle: Alma/SFX Local Collection
Publisher: Kidlington: Elsevier Ltd
ID: ISSN: 0140-6736
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title: Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
format: Article
creator:
  • Smoller, J.W
  • Craddock, N
  • Kendler, K
  • Lee, P.H
  • Neale, B.M
  • Nurnberger, J.I
  • Ripke, S
  • Santangelo, S
  • Sullivan, P.F
  • Buitelaar, J.K
  • Franke, B
  • et al
subjects:
  • 610 Medicine & health
  • Abridged Index Medicus
  • Adolescent Psychiatry
  • Adult
  • Age of Onset
  • Article
  • Attention Deficit Disorder with Hyperactivity
  • Attention Deficit Disorder with Hyperactivity - epidemiology
  • Attention Deficit Disorder with Hyperactivity - genetics
  • Attention deficit hyperactivity disorder
  • Autism
  • Behavior disorders
  • Biological and medical sciences
  • Bipolar Disorder
  • Bipolar Disorder - epidemiology
  • Bipolar Disorder - genetics
  • Brain
  • Calcium
  • Calcium Channels
  • Calcium channels (L-type)
  • Calcium channels (voltage-gated)
  • Calcium Channels, L-Type - genetics
  • Calcium signalling
  • Channel gating
  • Child
  • Child Development Disorders
  • Child Development Disorders, Pervasive - epidemiology
  • Child Development Disorders, Pervasive - genetics
  • Child psychopathology
  • Children
  • Children & youth
  • Chromosomes
  • Classification
  • Consortia
  • Datasets
  • Department of Child
  • Depression, Mental
  • Depressive Disorder
  • Depressive Disorder, Major - epidemiology
  • Depressive Disorder, Major - genetics
  • Diagnostic systems
  • Disease
  • Disorders
  • Enrichment
  • epidemiology
  • General aspects
  • Genes
  • Genetic aspects
  • Genetic effects
  • Genetic Loci
  • Genetic Loci - genetics
  • Genetic research
  • Genetic variation
  • Genetics
  • Genome-Wide Association Study
  • Genomes
  • Genomics
  • Genotypes
  • Government grants
  • Humans
  • Hyperactivity
  • Internal Medicine
  • L-Type
  • Loci
  • Logistic Models
  • Major
  • Medical research
  • Medical sciences
  • Medicin och hälsovetenskap
  • Medicine, Experimental
  • Mental depression
  • Mental disorders
  • Mental health
  • Mental illness
  • Neurosciences
  • Neurovetenskaper
  • Pervasive
  • Phenotypes
  • Physiological aspects
  • Polygenic inheritance
  • Polymorphism
  • Polymorphism, Single Nucleotide - genetics
  • Psychiatry
  • Psychopathology
  • Quantitative genetics
  • Quantitative trait loci
  • Regression analysis
  • Regression models
  • Risk analysis
  • Risk factors
  • Schizophrenia
  • Schizophrenia - epidemiology
  • Schizophrenia - genetics
  • Signal transduction
  • Single Nucleotide
  • Single nucleotide polymorphisms
  • Single-nucleotide polymorphism
  • Studies
ispartof: The Lancet (British edition), 2013, Vol.381 (9875), p.1371-1379
description: Summary 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
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
  • 1474-547X
url: Link


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titleIdentification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
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creatorSmoller, J.W ; Craddock, N ; Kendler, K ; Lee, P.H ; Neale, B.M ; Nurnberger, J.I ; Ripke, S ; Santangelo, S ; Sullivan, P.F ; Buitelaar, J.K ; Franke, B ; et al
creatorcontribSmoller, J.W ; Craddock, N ; Kendler, K ; Lee, P.H ; Neale, B.M ; Nurnberger, J.I ; Ripke, S ; Santangelo, S ; Sullivan, P.F ; Buitelaar, J.K ; Franke, B ; et al ; Cross-Disorder Group of the Psychiatric Genomics Consortium ; Sahlgrenska akademin ; Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi ; Göteborgs universitet ; Gothenburg University ; Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry ; Sahlgrenska Academy
descriptionSummary 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. Funding National Institute of Mental Health.
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0ISSN: 0140-6736
1ISSN: 1474-547X
2EISSN: 1474-547X
3DOI: 10.1016/S0140-6736(12)62129-1
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languageeng
publisherKidlington: Elsevier Ltd
subject610 Medicine & health ; Abridged Index Medicus ; Adolescent Psychiatry ; Adult ; Age of Onset ; Article ; Attention Deficit Disorder with Hyperactivity ; Attention Deficit Disorder with Hyperactivity - epidemiology ; Attention Deficit Disorder with Hyperactivity - genetics ; Attention deficit hyperactivity disorder ; Autism ; Behavior disorders ; Biological and medical sciences ; Bipolar Disorder ; Bipolar Disorder - epidemiology ; Bipolar Disorder - genetics ; Brain ; Calcium ; Calcium Channels ; Calcium channels (L-type) ; Calcium channels (voltage-gated) ; Calcium Channels, L-Type - genetics ; Calcium signalling ; Channel gating ; Child ; Child Development Disorders ; Child Development Disorders, Pervasive - epidemiology ; Child Development Disorders, Pervasive - genetics ; Child psychopathology ; Children ; Children & youth ; Chromosomes ; Classification ; Consortia ; Datasets ; Department of Child ; Depression, Mental ; Depressive Disorder ; Depressive Disorder, Major - epidemiology ; Depressive Disorder, Major - genetics ; Diagnostic systems ; Disease ; Disorders ; Enrichment ; epidemiology ; General aspects ; Genes ; Genetic aspects ; Genetic effects ; Genetic Loci ; Genetic Loci - genetics ; Genetic research ; Genetic variation ; Genetics ; Genome-Wide Association Study ; Genomes ; Genomics ; Genotypes ; Government grants ; Humans ; Hyperactivity ; Internal Medicine ; L-Type ; Loci ; Logistic Models ; Major ; Medical research ; Medical sciences ; Medicin och hälsovetenskap ; Medicine, Experimental ; Mental depression ; Mental disorders ; Mental health ; Mental illness ; Neurosciences ; Neurovetenskaper ; Pervasive ; Phenotypes ; Physiological aspects ; Polygenic inheritance ; Polymorphism ; Polymorphism, Single Nucleotide - genetics ; Psychiatry ; Psychopathology ; Quantitative genetics ; Quantitative trait loci ; Regression analysis ; Regression models ; Risk analysis ; Risk factors ; Schizophrenia ; Schizophrenia - epidemiology ; Schizophrenia - genetics ; Signal transduction ; Single Nucleotide ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Studies
ispartofThe Lancet (British edition), 2013, Vol.381 (9875), p.1371-1379
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0Smoller, J.W
1Craddock, N
2Kendler, K
3Lee, P.H
4Neale, B.M
5Nurnberger, J.I
6Ripke, S
7Santangelo, S
8Sullivan, P.F
9Buitelaar, J.K
10Franke, B
11et al
12Cross-Disorder Group of the Psychiatric Genomics Consortium
13Sahlgrenska akademin
14Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
15Göteborgs universitet
16Gothenburg University
17Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
18Sahlgrenska Academy
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0Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
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descriptionSummary 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. Funding National Institute of Mental Health.
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0610 Medicine & health
1Abridged Index Medicus
2Adolescent Psychiatry
3Adult
4Age of Onset
5Article
6Attention Deficit Disorder with Hyperactivity
7Attention Deficit Disorder with Hyperactivity - epidemiology
8Attention Deficit Disorder with Hyperactivity - genetics
9Attention deficit hyperactivity disorder
10Autism
11Behavior disorders
12Biological and medical sciences
13Bipolar Disorder
14Bipolar Disorder - epidemiology
15Bipolar Disorder - genetics
16Brain
17Calcium
18Calcium Channels
19Calcium channels (L-type)
20Calcium channels (voltage-gated)
21Calcium Channels, L-Type - genetics
22Calcium signalling
23Channel gating
24Child
25Child Development Disorders
26Child Development Disorders, Pervasive - epidemiology
27Child Development Disorders, Pervasive - genetics
28Child psychopathology
29Children
30Children & youth
31Chromosomes
32Classification
33Consortia
34Datasets
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36Depression, Mental
37Depressive Disorder
38Depressive Disorder, Major - epidemiology
39Depressive Disorder, Major - genetics
40Diagnostic systems
41Disease
42Disorders
43Enrichment
44epidemiology
45General aspects
46Genes
47Genetic aspects
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49Genetic Loci
50Genetic Loci - genetics
51Genetic research
52Genetic variation
53Genetics
54Genome-Wide Association Study
55Genomes
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58Government grants
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61Internal Medicine
62L-Type
63Loci
64Logistic Models
65Major
66Medical research
67Medical sciences
68Medicin och hälsovetenskap
69Medicine, Experimental
70Mental depression
71Mental disorders
72Mental health
73Mental illness
74Neurosciences
75Neurovetenskaper
76Pervasive
77Phenotypes
78Physiological aspects
79Polygenic inheritance
80Polymorphism
81Polymorphism, Single Nucleotide - genetics
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83Psychopathology
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85Quantitative trait loci
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91Schizophrenia - epidemiology
92Schizophrenia - genetics
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titleIdentification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
authorSmoller, J.W ; Craddock, N ; Kendler, K ; Lee, P.H ; Neale, B.M ; Nurnberger, J.I ; Ripke, S ; Santangelo, S ; Sullivan, P.F ; Buitelaar, J.K ; Franke, B ; et al
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0610 Medicine & health
1Abridged Index Medicus
2Adolescent Psychiatry
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4Age of Onset
5Article
6Attention Deficit Disorder with Hyperactivity
7Attention Deficit Disorder with Hyperactivity - epidemiology
8Attention Deficit Disorder with Hyperactivity - genetics
9Attention deficit hyperactivity disorder
10Autism
11Behavior disorders
12Biological and medical sciences
13Bipolar Disorder
14Bipolar Disorder - epidemiology
15Bipolar Disorder - genetics
16Brain
17Calcium
18Calcium Channels
19Calcium channels (L-type)
20Calcium channels (voltage-gated)
21Calcium Channels, L-Type - genetics
22Calcium signalling
23Channel gating
24Child
25Child Development Disorders
26Child Development Disorders, Pervasive - epidemiology
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37Depressive Disorder
38Depressive Disorder, Major - epidemiology
39Depressive Disorder, Major - genetics
40Diagnostic systems
41Disease
42Disorders
43Enrichment
44epidemiology
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46Genes
47Genetic aspects
48Genetic effects
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50Genetic Loci - genetics
51Genetic research
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60Hyperactivity
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71Mental disorders
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74Neurosciences
75Neurovetenskaper
76Pervasive
77Phenotypes
78Physiological aspects
79Polygenic inheritance
80Polymorphism
81Polymorphism, Single Nucleotide - genetics
82Psychiatry
83Psychopathology
84Quantitative genetics
85Quantitative trait loci
86Regression analysis
87Regression models
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89Risk factors
90Schizophrenia
91Schizophrenia - epidemiology
92Schizophrenia - genetics
93Signal transduction
94Single Nucleotide
95Single nucleotide polymorphisms
96Single-nucleotide polymorphism
97Studies
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15Göteborgs universitet
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jtitleThe Lancet (British edition)
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Smoller, J.W
1Craddock, N
2Kendler, K
3Lee, P.H
4Neale, B.M
5Nurnberger, J.I
6Ripke, S
7Santangelo, S
8Sullivan, P.F
9Buitelaar, J.K
10Franke, B
11et al
aucorp
0Cross-Disorder Group of the Psychiatric Genomics Consortium
1Sahlgrenska akademin
2Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
3Göteborgs universitet
4Gothenburg University
5Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
6Sahlgrenska Academy
formatjournal
genrearticle
ristypeJOUR
atitleIdentification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
jtitleThe Lancet (British edition)
addtitleLancet
date2013
risdate2013
volume381
issue9875
spage1371
epage1379
pages1371-1379
issn
00140-6736
11474-547X
eissn1474-547X
codenLANCAO
notesMembers listed at end of paper
abstractSummary 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. Funding National Institute of Mental Health.
copKidlington
pubElsevier Ltd
pmid23453885
doi10.1016/S0140-6736(12)62129-1
oafree_for_read