Nadine M Melhem1, Sami Hamdan, Lambertus Klei, Shawn Wood, Jamie Zelazny, Amos Frisch, Abraham Weizman, Miri Carmel, Elena Michaelovsky, Ilana Farbstein, Danuta Wasserman, Muhammad El-Heib, Robert Ferrell, Alan Apter, Bernie Devlin, David Brent. 1. aDepartment of Psychiatry, University of Pittsburgh School of Medicine bDepartment of Human Genetics cUniversity of Pittsburgh Medical Center, Pittsburgh, Pennsylvania dAcademic College of Tel Aviv-Jaffa, School of Behavioral Sciences eFelsenstein Medical Research Center fSackler Faculty of Medicine, Tel Aviv University, Tel Aviv gGeha Mental Health Center hScheiner Children's Medical Center of Israel, Petah Tikvah iDepartment of Child and Adolescent Psychiatry, Ziv Medical Center, Safed jMinistry of Education, Jerusalem, Israel kNational Centre for Suicide Research and Prevention of Mental ill-Health (NASP), Karolinska Institute, Stockholm, Sweden.
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.
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.
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Authors: J John Mann; Victoria A Arango; Shelli Avenevoli; David A Brent; Frances A Champagne; Paula Clayton; Dianne Currier; Donald M Dougherty; Fatemah Haghighi; Susan E Hodge; Joel Kleinman; Thomas Lehner; Francis McMahon; Eve K Mościcki; Maria A Oquendo; Ganshayam N Pandey; Jane Pearson; Barbara Stanley; Joseph Terwilliger; Amy Wenzel Journal: Biol Psychiatry Date: 2009-02-07 Impact factor: 13.382