Assessment of Whole-Exome Sequence Data in Attempted Suicide within a Bipolar Disorder Cohort

Abstract

Suicidal behavior is a complex and devastating phenotype with a heritable component that has not been fully explained by existing common genetic variant analyses. This study represents the first large-scale DNA sequencing project designed to assess the role of rare functional genetic variation in suicidal behavior risk. To accomplish this, whole-exome sequencing data for ∼19,000 genes were generated for 387 bipolar disorder subjects with a history of suicide attempt and 631 bipolar disorder subjects with no prior suicide attempts. Rare functional variants were assessed in all exome genes as well as pathways hypothesized to contribute to suicidal behavior risk. No result survived conservative Bonferroni correction, though many suggestive findings have arisen that merit additional attention. In addition, nominal support for past associations in genes, such as BDNF, and pathways, such as the hypothalamic-pituitary-adrenal axis, was also observed. Finally, a novel pathway was identified that is driven by aldehyde dehydrogenase genes. Ultimately, this investigation explores variation left largely untouched by existing efforts in suicidal behavior, providing a wealth of novel information to add to future investigations, such as meta-analyses.

Machine learning for genetic prediction of psychiatric disorders: a systematic review

“…e: part of the Critical Assessment of Genome Interpretation (CAGI)-4 challenge. Laksshman et al [24] reference Daneshjou et al [25], from which a third reference [26] gives information on an exome dataset with only bipolar cases recruited for a suicide study, but not controls. f: Whole-Genome Association Study of Bipolar Disorder, dbGaP study accession "phs000017.v3.p1".…”

Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

“…In this CAGI 4 challenge, 1,000 exomes of unrelated bipolar disorder cases and age/ancestry‐matched controls of Northern European ancestry were provided. Five‐hundred exomes were used as the training set and 500 exomes were used for the prediction set (Monson et al., ). Groups were asked to report a probability of bipolar disorder (between 0 and 1) for each individual and a standard deviation representing their confidence in that prediction.…”

A targeted sequencing study of glutamatergic candidate genes in suicide attempters with bipolar disorder

“…However, there is also an independent factor contributing to the heritability of suicidal behavior. We previously conducted a whole exome sequencing study of bipolar suicide attempters and bipolar non-attempters to assess this independent factor [Monson et al, 2016]. This whole exome study implicated glutamatergic neurotransmission in attempted suicide, as did our genome-wide association study (GWAS) of the attempted suicide phenotype [Willour et al, 2012].…”