Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined...

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Published inMolecular psychiatry Vol. 18; no. 2; pp. 195 - 205
Main Authors Chen, D T, Jiang, X, Akula, N, Shugart, Y Y, Wendland, J R, Steele, C J M, Kassem, L, Park, J-H, Chatterjee, N, Jamain, S, Cheng, A, Leboyer, M, Muglia, P, Schulze, T G, Cichon, S, Nöthen, M M, Rietschel, M, McMahon, F J
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.02.2013
Nature Publishing Group
Subjects
631/208/205/2138
692/699/476/1333
692/700/478/174
Adult and adolescent clinical studies
Ankyrins - genetics
Ankyrins - metabolism
Antidepressive Agents - pharmacology
Asian Continental Ancestry Group - genetics
Behavioral Sciences
Biological and medical sciences
Biological Psychology
Bipolar disorder
Bipolar Disorder - ethnology
Bipolar Disorder - genetics
Bipolar disorders
Cell Line, Transformed
Chromosome 3
Cytokines - genetics
Dose-Response Relationship, Drug
European Continental Ancestry Group - genetics
Female
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Gene Frequency
Genetic analysis
Genetic aspects
Genetic markers
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Genomes
Health aspects
Human health and pathology
Humans
Lectins - genetics
Lectins - metabolism
Life Sciences
Lithium Chloride - pharmacology
Male
Medical sciences
Medicine
Medicine & Public Health
Membrane Transport Proteins - genetics
Membrane Transport Proteins - metabolism
Meta-analysis
Meta-Analysis as Topic
Mood disorders
Neurosciences
original-article
Pharmacotherapy
Polymorphism, Single Nucleotide
Psychiatrics and mental health
Psychiatry
Psychological aspects
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Receptors, Prostaglandin - genetics
Receptors, Prostaglandin - metabolism
RNA, Messenger - metabolism
Single-nucleotide polymorphism
Size distribution
Systematic review
Time Factors
Valproic Acid - pharmacology
Canada
France
United States
Germany
meta-analysis
TRANK1
bipolar disorder
ANK3
3p21
LBA1
Mood disorder
Concomitant disease
Asiatic
Bipolar disorder
Review
Ethnic group
Metaanalysis
Online AccessGet full text

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Abstract Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 ( LBA1 ), LMAN2L and PTGFR . In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1 , was significant at the P =2.4 × 10 −11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
AbstractList Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10−11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ~750000 high-quality genetic markers on a combined sample of ~14000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ~17700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P =2.4 x [10.sup.-11] level, with no heterogeneity. Supportive evidence for prior association findings near ANK3and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that > 63 000 case-control samples would be needed to identify the ~105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10-11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ~750000 high-quality genetic markers on a combined sample of ~14000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ~17700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P =2.4 x [10.sup.-11] level, with no heterogeneity. Supportive evidence for prior association findings near ANK3and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that > 63 000 case-control samples would be needed to identify the ~105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD. Molecular Psychiatry (2013) 18,195-205; doi: 10.1038/mp.2011.157; published online 20 December 2011 Keywords: ANK3; bipolar disorder; LBA1; meta-analysis; TRANK1; 3p21
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of similar to 750 000 high-quality genetic markers on a combined sample of similar to 14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of similar to 17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 10 super(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case-control samples would be needed to identify the similar to 105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 ( LBA1 ), LMAN2L and PTGFR . In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1 , was significant at the P =2.4 × 10 −11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that \textgreater63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain \textless6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.
Audience Academic
Author Jiang, X
Cichon, S
Nöthen, M M
Shugart, Y Y
Wendland, J R
Park, J-H
Leboyer, M
Jamain, S
Kassem, L
Akula, N
Muglia, P
Cheng, A
Rietschel, M
Chatterjee, N
Steele, C J M
McMahon, F J
Chen, D T
Schulze, T G
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2015 INIST-CNRS
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Keywords meta-analysis
TRANK1
bipolar disorder
ANK3
3p21
LBA1
Mood disorder
Concomitant disease
Asiatic
Bipolar disorder
Review
Ethnic group
Metaanalysis
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Snippet Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry...
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SubjectTerms 631/208/205/2138
692/699/476/1333
692/700/478/174
Adult and adolescent clinical studies
Ankyrins - genetics
Ankyrins - metabolism
Antidepressive Agents - pharmacology
Asian Continental Ancestry Group - genetics
Behavioral Sciences
Biological and medical sciences
Biological Psychology
Bipolar disorder
Bipolar Disorder - ethnology
Bipolar Disorder - genetics
Bipolar disorders
Cell Line, Transformed
Chromosome 3
Cytokines - genetics
Dose-Response Relationship, Drug
European Continental Ancestry Group - genetics
Female
Gene Expression Regulation - drug effects
Gene Expression Regulation - genetics
Gene Frequency
Genetic analysis
Genetic aspects
Genetic markers
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Genomes
Health aspects
Human health and pathology
Humans
Lectins - genetics
Lectins - metabolism
Life Sciences
Lithium Chloride - pharmacology
Male
Medical sciences
Medicine
Medicine & Public Health
Membrane Transport Proteins - genetics
Membrane Transport Proteins - metabolism
Meta-analysis
Meta-Analysis as Topic
Mood disorders
Neurosciences
original-article
Pharmacotherapy
Polymorphism, Single Nucleotide
Psychiatrics and mental health
Psychiatry
Psychological aspects
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Receptors, Prostaglandin - genetics
Receptors, Prostaglandin - metabolism
RNA, Messenger - metabolism
Single-nucleotide polymorphism
Size distribution
Systematic review
Time Factors
Valproic Acid - pharmacology
Title Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder
URI https://link.springer.com/article/10.1038/mp.2011.157
https://www.ncbi.nlm.nih.gov/pubmed/22182935
https://www.proquest.com/docview/1272332597
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https://www.proquest.com/docview/1282043637
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https://inserm.hal.science/inserm-04274211
Volume 18
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