Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder.
paper
Cited
Public
- Authors
- Xie, Pingxing; Kranzler, Henry R; Yang, Can; Zhao, Hongyu; Farrer, Lindsay A; Gelernter, Joel
- Year
- 2013
- Journal
- Biological psychiatry
- PMID
- 23726511
- DOI
- 10.1016/j.biopsych.2013.04.013
- PMCID
- PMC3810148
BACKGROUND: Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate gene association studies have identified few genetic variants that contribute to PTSD risk. METHODS: We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis. RESULTS: In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance (p = 3.97 Γ 10(-8)). A SNP that maps to the first intron of the Tolloid-Like 1 gene (TLL1) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1, rs6812849 and rs7691872, with p values of 6.3 Γ 10(-6) and 2.3 Γ 10(-4), respectively. In the combined sample, rs6812849 had a p value of 3.1Γ10(-9). No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results. CONCLUSIONS: This study identified TLL1 as a new susceptibility gene for PTSD.
Quintile-Quintile plots for whole cohort of European Americans (A), European Americans with trauma experiences (B), whole cohort of African Americans (C), and African Americans with trauma experiences (D). The genomic inflation factor (Ξ») is the ratio of the observed median p value to its expected value.
Regional Manhattan plots of the top two strongest association regions in European Americans: chromosome 7p12 (A) and chromosome 4q32 (B). The single nucleotide polymorphisms are color coded based on the linkage disequilibrium with the most significant single nucleotide polymorphism in each region, rs406001 and rs6812849, respectively.
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| Name | Type |
|---|---|
| 2752 subjects with AIMs local | cohort |
| 3112 follow-up subjects local | cohort |
| 360 subjects without AIMs local | cohort |
| 5504 GWAS subjects local | cohort |
| 5799 GWAS subjects local | cohort |
| AA | cohort |
| ADCYAP1R1 | gene |
| adult mice | cohort |
| African American | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Bdnf | gene |
| brain development | phenotype |
| cases | cohort |
| cerebellum | anatomy |
| cocaine | phenotype |
| combined sample | cohort |
| control subjects | cohort |
| Cordon-Bleu local | gene |
| Decreased cerebellar volume local | phenotype |
| EA population | cohort |
| EAs | cohort |
| European ancestry | cohort |
| Fkbp5 | gene |
| Gabbr2 | gene |
| glucocorticoids | drug |
| Granular layer of cerebellum local | anatomy |
| GWAS | cohort |
| GWAS AA subjects local | cohort |
| GWAS subjects local | cohort |
| hippocampus | anatomy |
| Juvenile mice local | cohort |
| learning and memory | phenotype |
| lifetime psychiatric disorders | phenotype |
| McLean Hospital | cohort |
| Medical University of South Carolina | cohort |
| mice | cohort |
| Ndrg1 | gene |
| neurogenesis | phenotype |
| opioid | drug |
| opioid dependence | phenotype |
| physical abuse | phenotype |
| posttraumatic stress disorder | phenotype |
| Post-Traumatic Stress Disorder | phenotype |
| Primary GWAS cohort local | cohort |
| Pro-BDNF local | drug |
| PTSD control subjects local | cohort |
| quality_control_failure local | phenotype |
| replication sample | cohort |
| RORA | gene |
| rs13006863 local | variant |
| rs1503292 local | variant |
| rs2272651 local | variant |
| rs2779551 local | variant |
| rs382903 local | variant |
| rs406001 local | variant |
| rs450378 local | variant |
| rs6812849 local | variant |
| rs7014900 local | variant |
| rs7691872 local | variant |
| SLC4A5 local | gene |
| SNP | cohort |
| SSADDA cohort local | cohort |
| stress hormones | drug |
| stress response | phenotype |
| study cohort | cohort |
| substance use | phenotype |
| TLL1 | gene |
| trauma-exposed subjects local | cohort |
| trauma exposure | phenotype |
| TRPS1 | gene |
| University of Connecticut Health Center | cohort |
| University of Pennsylvania | cohort |
| Yale University School of Medicine | cohort |
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