A Genomewide Linkage Study on Suicidality in Major Depressive Disorder Confirms Evidence for Linkage to 2p12

Suicidal behavior is commonly associated with depression. Twin studies indicate that both suicidality and major depressive disorder (MDD) are heritable. However, epidemiological evidence suggests that the inheritance of suicidality is likely to be independent of the underlying psychiatric disorder, implying a distinct genetic contribution to suicidality. We conducted a genomewide linkage search aiming to detect genomic loci that may harbor susceptibility genes contributing to risk for suicidality in recurrent MDD. Affected sibling pair (ASP) variance components analysis was performed using the Depression Network cohort of 971 ASPs. The quantitative trait measuring suicidality as a broad phenotype, encompassing ideation and suicide attempts, was established from Schedules for Clinical Assessment in Neuropsychiatry interview items. We examined 1,060 genotyped microsatellite markers with an average spacing of 3.3 cM. Empirical thresholds for linkage evidence were set by whole-genome simulations (LOD=2.71 for genomewide significance, 1.71 for suggestive linkage). No genomewide significant findings were found. Marker D3S1234 on 3p14 achieved suggestive linkage and yielded a maximum LOD of 1.853 (P=0.0017), loci 9p24.3 and 18q22-q23 achieved LOD scores > 1.5. We found some support for linkage to 2p12 (LOD=1.2, P=0.0087) which was previously implicated in linkage studies of suicidality. Our follow-up meta-analysis of five studies showed strong linkage to this region (P-2 x 10(-6)). In conclusion, this study analyzed suicidality as a continuous trait in MDD. We found modest evidence for linkage on 3p14. Our meta-analysis supports previous evidence of linkage to suicidality on 2p12. Some candidate genes in these regions may plausibly be implicated in suicidality. (C) 2010 Wiley-Liss, Inc.