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Multimarker analysis suggests the involvement of BDNF signaling and microRNA biosynthesis in suicidal behavior
Author(s) -
Pulay Attila J.,
Réthelyi János M.
Publication year - 2016
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.32433
Subject(s) - suicidal ideation , bipolar disorder , candidate gene , mood disorders , suicide attempt , genome wide association study , genetic association , single nucleotide polymorphism , depression (economics) , heritability , clinical psychology , genetics , mood , oncology , gene , medicine , psychiatry , psychology , biology , poison control , genotype , suicide prevention , anxiety , environmental health , macroeconomics , economics
Despite moderate heritability estimates the genetics of suicidal behavior remains unclear, genome‐wide association and candidate gene studies focusing on single nucleotide associations reported inconsistent findings. Our study explored biologically informed, multimarker candidate gene associations with suicidal behavior in mood disorders. We analyzed the GAIN Whole Genome Association Study of Bipolar Disorder version 3 (n = 999, suicidal n = 358) and the GAIN Major Depression: Stage 1 Genomewide Association in Population‐Based Samples (n = 1,753, suicidal n = 245) datasets. Suicidal behavior was defined as severe suicidal ideation or attempt. Candidate genes were selected based on literature search (Geneset1, n = 35), gene expression data of microRNA genes, (Geneset2, n = 68) and their target genes (Geneset3, n = 11,259). Quality control, dosage analyses were carried out with PLINK. Gene‐based associations of Geneset1 were analyzed with KGG. Polygenic profile scores of suicidal behavior were computed in the major depression dataset both with PRSice and LDpred and validated in the bipolar disorder data. Several nominally significant gene‐based associations were detected, but only DICER1 associated with suicidal behavior in both samples, while only the associations of NTRK2 in the depression sample reached family wise and experiment wise significance. Polygenic profile scores negatively predicted suicidal behavior in the bipolar sample for only Geneset2, with the strongest prediction by PRSice at P t < 0.03 (Nagelkerke R 2 = 0.01, P < 0.007). Gene‐based association results confirmed the potential involvement of the BDNF‐NTRK2‐CREB pathway in the pathogenesis of suicide and the cross‐disorder association of DICER1. Polygenic risk prediction of the selected miRNA genes indicates that the miRNA system may play a mediating role, but with considerable pleiotropy. © 2016 Wiley Periodicals, Inc.