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

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.>0.1, r2>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

LD-plot of the region of interest in PCLO.

<p>The SNPs with the lowest P-values, rs2715147 and rs2715148 are in high LD with eachother and with rs2522833. This supports the hypothesis that either rs2522833 or a SNP in high LD with it is the most likely causal variant in this cohort.</p

Base pairs and percentage of region covered on the Sequence Capture arrays.

<p>Base pairs and percentage of region covered on the Sequence Capture arrays.</p

Haplotypes constructed using PLINK and their respective P-values.

<p>Haplotypes constructed using PLINK and their respective P-values.</p

The number of SNPs used for the epistasis analysis.

<p>The number of SNPs used for the epistasis analysis.</p

The LD-structure of <i>PCLO</i>.

<p>The LD-structure of <i>PCLO</i> shown in an r²-plot created in Haploview. The plot shows the LD-block in which the SNPs with the lowest P-values were found. Non-synonymous coding SNP rs2522833, rs2715147 and rs2715148 are in high r² with each other.</p