Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.
paper
Cited
Public
- Authors
- Shyn, S I; Shi, J; Kraft, J B; Potash, J B; Knowles, J A; Weissman, M M; Garriock, H A; Yokoyama, J S; McGrath, P J; Peters, E J; Scheftner, W A; Coryell, W; Lawson, W B; Jancic, D; Gejman, P V; Sanders, A R; Holmans, P; Slager, S L; Levinson, D F; Hamilton, S P
- Year
- 2011
- Journal
- Molecular psychiatry
- PMID
- 20038947
- DOI
- 10.1038/mp.2009.125
- PMCID
- PMC2888856
We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500βK, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10β»β·), SP4 (P=7.68 x 10β»β·) and GRM7 (P=1.11 x 10β»βΆ). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.
Overview of STAR*D GWAS results for 260,474 SNPs(A) Q-Q plot of observed vs. expected -log (P-value). Ξ», the genomic inflation factor, is estimated at 1.022. (B) Manhattan plot of all results by chromosomal location.
Meta-analysis resultsShown are association test results (-log10[P-values] on the Y-axis) for the meta-analyses of the GenRED, STAR*D and GAIN MDD datasets, for the Broad phenotype (primary analysis) and the Narrow phenotype (recurrent early-onset cases). The X-axis shows the start position of each chromosome. Plots for males and females separately are available in online Supplementary Figures S15 and S16.
Best-supported regions in the meta-analysisShown are plots of association test results (males+females unless noted otherwise) for the three gene-containing regions with the lowest P-values in the primary (Broad) meta-analysis (see Table 5): ATP6V1B2 (Panel A), SP4 (B), GRM7 (C). Shown in each panel from top to bottom are: an ideogram of the chromosome with the plotted area marked in red; locations in base pairs; RefSeq genes with arrows representing direction of transcription; association test results as the -log10 of the P-value for each genotyped and imputed SNP; and color-coded marker-marker linkage disequiibrium results for phased HapMap II CEU genotypes (UCSC browser). Similar plots for additional top findings are available as online Supplementary Figures.
| Name | Type |
|---|---|
| 12 cases local | cohort |
| 500K28 local | drug |
| ADRBK2 local | gene |
| Affy 5.0 local | drug |
| Affymetrix 500K local | drug |
| Affymetrix 6.0 | drug |
| AMN082 local | drug |
| ANKRD46 local | gene |
| antidepressants | drug |
| antimanic drugs local | drug |
| anxiety | phenotype |
| ATP6V1B2 local | gene |
| ATP6V1G1 local | gene |
| autism | phenotype |
| bipolar disorder | phenotype |
| bipolar I disorder | phenotype |
| blood pressure | phenotype |
| brain | anatomy |
| Broad local | phenotype |
| Broad analysis local | cohort |
| Broad phenotype local | phenotype |
| CACNA2D4 local | gene |
| cancer | phenotype |
| cases | cohort |
| CCDC109B local | gene |
| CEU HapMap haplotypes local | cohort |
| chr3p14.1 local | variant |
| chr3q26.32 local | variant |
| chr8q24.61_non-genic_SNPs local | variant |
| citalopram | drug |
| CLTCL1 | gene |
| contextual learning deficits local | phenotype |
| controls | cohort |
| copy number variants | variant |
| CSMD3 | gene |
| CTNND2 local | gene |
| datasets | cohort |
| dbGaP | cohort |
| decreased granule cell density local | phenotype |
| DYSF local | gene |
| ERBB2IP local | gene |
| estrogen receptors local | drug |
| European ancestry | cohort |
| European-ancestry controls local | cohort |
| FGF13 local | gene |
| frontal cortex | anatomy |
| GAIN-MDD | cohort |
| GAIN MDD dataset local | cohort |
| GAIN-MDD dataset local | cohort |
| GDNF | drug |
| genetic variants | cohort |
| GenRED local | cohort |
| GenRED cases local | cohort |
| GenRED dataset local | cohort |
| GenRED GWAS local | cohort |
| GenRED sample local | cohort |
| German clinical sample local | cohort |
| German/Swiss recurrent MDD GWAS local | cohort |
| glutamate-induced neurotoxicity local | phenotype |
| GRIA1 | gene |
| GRM7 | gene |
| GWAS | cohort |
| GWAS28 local | cohort |
| Hamilton Depression Rating local | phenotype |
| HapMap | cohort |
| HapMap II local | cohort |
| hippocampal dentate gyrus | anatomy |
| hippocampus | anatomy |
| Hispanic | phenotype |
| Histone gene cluster local | gene |
| imputed SNPs | variant |
| infertility local | phenotype |
| ITPK1 local | gene |
| KCTD14 local | gene |
| KIFAP3 local | gene |
| lithium | drug |
| LPHN2 local | gene |
| major depressive disorder | phenotype |
| male knockout mice local | cohort |
| MARK2 local | gene |
| MDD candidate genes local | gene |
| MDD phenotype local | phenotype |
| men | cohort |
| meta-analysis | cohort |
| MGS | anatomy |
| MGS controls local | cohort |
| MGS/GenRED controls local | cohort |
| Molecular Genetics of Schizophrenia (MGS) study local | cohort |
| mood disorders | phenotype |
| MSR1 local | gene |
| Narrow local | phenotype |
| Narrow analysis local | cohort |
| Narrow (recurrent early-onset) phenotype local | phenotype |
| Netherlands population-based samples local | cohort |
| neuroticism | phenotype |
| NIMH repository local | cohort |
| NIMH repository program local | cohort |
| NLGN4X | gene |
| NRXN3 | gene |
| PCLO | gene |
| Piccolo local | drug |
| PLEKHA7 local | gene |
| Psychiatric Genomics Consortium | cohort |
| RCOR2 local | gene |
| recurrent major depressive disorder | phenotype |
| restricting AN | phenotype |
| RPRM local | gene |
| rs12462886 local | variant |
| rs3788477 local | variant |
| schizoaffective disorder | phenotype |
| schizophrenia | phenotype |
| sensorimotor gating deficits local | phenotype |
| sex | phenotype |
| SLC18A1 local | gene |
| SLC5A12 local | gene |
| SNP | cohort |
| SP4 | gene |
| SRD5A2 local | gene |
| STAR*D local | cohort |
| substance use | phenotype |
| SV2B local | gene |
| Swiss population-based sample local | cohort |
| SYN3 local | gene |
| THRB local | gene |
| Twin registry local | cohort |
| Valproic acid | drug |
| White | phenotype |
| women | cohort |
| WTCCC bipolar disorder GWAS local | cohort |
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