Poor replication of candidate genes for major depressive disorder using genome-wide association data

Fokko Bosker (1) , Catharina Hartman (1) , Ilja Nolte (1) , Bram Prins (1) , D. Posthuma (1) , Tineke van Veen (1) , G. Willemsen (1) , Roel de Rijk (1) , Eco de Geus (1) , Witte Jg Hoogendijk (1) , Patrick Sullivan (1) , Brenda Penninx (1) , Dorret Boomsma (1) , Harold Snieder (1) , Willem Nolen (1) , Peter Terpstra (1)

1 Human Genetics Branch

Data from the GAIN genome-wide association study (GWAS) in major depressive disorder (MDD) were used to explore previously reported candidate gene and SNP associations in MDD. A systematic literature search of candidate genes associated with MDD in case-control studies was performed before the results of the GAIN MDD study became available. Measured and imputed candidate SNPs and genes were tested in the GAIN MDD study encompassing 1,738 cases and 1,802 controls. Imputation was used to increase the number of SNPs from the GWAS and to improve coverage of SNPs in the candidate genes selected. Tests were carried out for individual SNPs and the entire gene using different statistical approaches, with permutation analysis as the final arbiter. Seventy-eight papers reporting on 57 genes were identified, from which 92 SNPs could be mapped. In the GAIN MDD study, two SNPs were associated with MDD: C5orf20 (rs12520799; p=0.038; OR AT=1.10, 95% CI 0.95-1.29; OR TT=1.21, 95% CI 1.01-1.47), and NPY (rs16139; p=0.034; OR C allele=0.73, 95% CI 0.55-0.97) constituting a direct replication of previously identified SNPs. At the gene level, TNF (rs76917; OR T=1.35, 95%CI 1.13-1.63; p=0.0034) was identified as the only gene for which the association with MDD remained significant after correction for multiple testing. For SLC6A2 (NET) significantly more SNPs (19 out of 100; p=0.039) than expected w ere associated while accounting for the linkage disequilibrium structure. Thus, we found support for involvement in MDD for only 4 genes. However, given the number of candidate SNPs and genes that were tested, even these significant may well be false positives. The poor replication may point to publication bias and false-positive findings in previous candidate gene studies, but may also be related to heterogeneity of the MDD phenotype as well as contextual genetic or environmental factors.

Mots clés: candidate genes; genome-wide association study; major depressive disorder; replication; single nucleotide polymorphism

Fokko Bosker, Catharina Hartman, Ilja Nolte, Bram Prins, D. Posthuma, et al.. Poor replication of candidate genes for major depressive disorder using genome-wide association data. Molecular Psychiatry, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/mp.2010.38⟩. ⟨hal-00522166⟩