Causes of opioid-related deaths are multifactorial, so solutions must address prescriber behaviors, patient contributory factors, nonmedical use patterns, and systemic failures. Clinical strategies to reduce opioid-related mortality should be empirically tested, should not reduce access to needed therapies, should address risk from methadone as well as other opioids, and should be incorporated into any risk evaluation and mitigation strategies enacted by regulators.

We have used unique population-based data resources to identify 22 high-risk extended pedigrees that show clustering of suicide over twice that expected from demographically adjusted incidence rates. In this initial study of genetic risk factors, we focused on two high-risk pedigrees. In the first of these (pedigree 12), 10/19 (53%) of the related suicides were female, and the average age at death was 30.95. In the second (pedigree 5), 7/51 (14%) of the suicides were female and the average age at death was 36.90. Six decedents in pedigree 12 and nine in pedigree 5 were genotyped with the Illumina HumanExome BeadChip. Genotypes were analyzed using the Variant Annotation, Analysis, and Search program package that computes likelihoods of risk variants using the functional impact of the DNA variation, aggregative scoring of multiple variants across each gene and pedigree structure. We prioritized variants that were: (1) shared across pedigree members, (2) rare in other Utah suicides not related to these pedigrees, (3) ⩽ 5% in genotyping data from 398 other Utah population controls and (4) ⩽5% frequency in publicly available sequence data from 1358 controls and/or in dbSNP. Results included several membrane protein genes (ANO5, and TMEM141 for pedigree 12 and FAM38A and HRCT1 for pedigree 5). Other genes with known neuronal involvement and/or previous associations with psychiatric conditions were also identified, including NFKB1, CASP9, PLXNB1 and PDE11A in pedigree 12, and THOC1, and AUTS2 in pedigree 5. Although the study is limited to variants included on the HumanExome BeadChip, these findings warrant further exploration, and demonstrate the utility of this high-risk pedigree resource to identify potential genes or gene pathways for future development of targeted interventions.

Use of pain medication outside prescription bounds was a risk factor for death. However, decedents were more likely to have had chronic pain, and the majority of both groups had obtained pain medication by prescription. Other factors (e.g., smoking status) might also play important roles in prescription opioid-related death. Prescribers should screen chronic pain patients for risk factors.

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