Genomewide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide

Abstract

Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have >4,500 DNA samples from completed suicides through a collaboration with the Utah Medical Examiner. We have linked the records from these cases to the Utah Population Database which includes multi-generation genealogies, demographic data, and medical information on over 8 million individuals. This linking has resulted in extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed DNA from 215 suicide cases in 43 of our largest high-risk families and identified 16 regions with genome-wide significance in 10 families. Of the 163 genes in these regions, 25% were associated with psychiatric risk. We also found 13 regions with genome-wide suggestive evidence where the region overlaps in >1 family (p-values from 4.63E-09 to <1E-16). Of the 101 genes in these overlapping regions, seven have been previously associated with suicide risk (RGS18, BRINP3, RHEB, CDK5, CTNNA3, STAT1, and HTR2A); only one gene with specific suicide risk would have been expected by chance. Our most significant region on chromosome 5q23.3 was shared by 21 cases across three families. This region contains several genes associated with both psychiatric conditions and inflammation: HINT1, RAPGEF6, ACSL6, IL3, SLC22A4, CSF2, and IRF1. Our study provides 249 genes in the significant regions in our study represent important new candidate genes for suicide. The genome-wide significant family-specific regions may reveal more rare risk variants, while risk variants in regions that overlap across families may be more common.. CC-BY-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/195644 doi: bioRxiv preprint first posted online Sep. 28, 2017; 3 Author SummarySuicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests that genetic factors play a major role in completed suicide. We have used DNA from suicide cases related to each other in very large extended high-risk families (7-9 generations) to discover regions of the genome likely to contain genetic changes leading to increased suicide risk. Studying these distantly related cases minimizes effects of shared environment and allows us to detect genetic risks more easily through their familial repetition. The genomic regions discovered in this study of our 43 largest high-risk families contained seven genes with corroborating evidence of association with suicide from previous studies, in addition to many genes with known psychiatric assoc...

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