A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

作者：Verbeek Eva C^*; Bakker Ingrid M C; Bevova Marianna R; Bochdanovits Zoltan; Rizzu Patrizia; Sondervan David; Willemsen Gonneke; de Geus Eco J; Smit Johannes H; Penninx Brenda W; Boomsma Dorret I; Hoogendijk Witte J G; Heutink Peter

来源：PLos One, 2012, 7(5): e37384.

DOI：10.1371/journal.pone.0037384

Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f %26gt; 0.1, r(2)%26gt; 0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P=6.8E-7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P=1.2E-6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P=9.9E-7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.

• 出版日期2012-5-23