Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred

Abstract

Objectives 

Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and runs of homozygosity (ROH) are associated with an increased risk for disease phenotypes, including schizophrenia and other psychiatric disorders. The effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt (SA) were quantified in an Arab Bedouin Kindred.

Methods 

We carried out genetic analyses of 439 individuals from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of SAs and first-degree relatives of individuals who have attempted or died by suicide.

Results 

We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these individuals, two-fold higher than ROH rates for individuals from populations of European ancestry. Inbreeding and total length of ROH were not associated with risk for depression or attempt. For CNVs, an increased number of duplications more than 500 kb was associated with an increased risk for attempt (odds ratio: 2.9; P=0.01; 95% confidence interval: 1.3–6.6). Although not significant after correction for multiple testing, the risk for SA appears to increase with copy number for a CNV on chromosome 9p24.1. This possibility is intriguing because the CNV covers GLDC, which encodes glycine dehydrogenase that binds to glycine, a co-agonist at N-methyl-D-aspartate glutamate receptors, and is involved in glutamatergic neurotransmission.

Conclusion 

Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase the risk for several neuropsychiatric disorders, including depression and SA, irrespective of ancestry.