Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.
Runs of homozygosity, copy number variation, and risk for depression and suicidal behavior in an Arab Bedouin kindred.
复制标题
阿拉伯贝都因人的纯合性，拷贝数变化以及抑郁和自杀行为的风险。
DOI：
10.1097/ypg.0000000000000177
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发表时间：
2017-10
影响因子：
0.9
通讯作者：
Brent D
中科院分区：
文献类型：
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作者：
Melhem NM;Hamdan S;Klei L;Wood S;Zelazny J;Frisch A;Weizman A;Carmel M;Michaelovsky E;Farbstein I;Wasserman D;El-Heib M;Ferrell R;Apter A;Devlin B;Brent D
近亲繁殖增加了有害等位基因纯合的概率。近亲繁殖和纯合性缺失（ROH）与疾病表型的风险增加有关，包括精神分裂症和其他精神疾病。在阿拉伯贝都因人亲属中，对近亲繁殖、ROH、纯合缺失和其他拷贝数变异（CNVs）对抑郁症和自杀企图风险的影响进行了量化。我们对439名来自阿拉伯家族的受试者进行了遗传分析，这些受试者具有高比例的抑郁症和自杀行为。我们完全确定了自杀未遂者和自杀未遂或自杀死亡者的一级亲属。我们发现了大量的ROH区域。平均而言，这些受试者的基因组的5%被ROH覆盖，比来自欧洲血统人群的受试者的ROH率高两倍。近亲繁殖和ROH的总长度与抑郁或尝试的风险无关。对于CNVs，>500 kb的重复数增加与尝试风险增加相关（OR=2.9，p=0.01; 95% CI 1.3，6.6）。虽然在多次测试校正后不显著，但自杀企图的风险似乎随着染色体9p24.1上的CNV拷贝数的增加而增加。这种可能性是有趣的，因为CNV涵盖了GLDC，其编码与甘氨酸结合的甘氨酸脱氢酶，甘氨酸是N-甲基-D-天冬氨酸（NMDA）谷氨酸受体的共激动剂，并参与谷氨酸能神经传递。我们的研究结果增加了越来越多的证据表明，遗传风险因素具有多效性，可增加几种神经精神疾病的风险，包括抑郁症和自杀企图，无论其血统如何。
Inbreeding increases the probability of homozygosity of deleterious alleles. Inbreeding and Runs of homozygosity (ROH) are associated with increased risk for disease phentoypes, including schizophrenia and other psychiatric disorders. Effects of inbreeding, ROH, homozygous deletions, and other copy number variations (CNVs) on risk for depression and suicide attempt were quantified in an Arab Bedouin Kindred. We performed genetic analyses of 439 subjects from an Arab kindred with high rates of depression and suicidal behavior. We obtained complete ascertainment of suicide attempters and first-degree relatives of subjects who have attempted or died by suicide. We found extensive regions of ROH. On average, 5% of the genome is covered by ROH for these subjects, twofold higher than ROH rates for subjects 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 >500 kb was associated with increased risk for attempt (OR=2.9, p=0.01; 95% CI 1.3, 6.6). While not significant after correction for multiple testing, risk for suicide attempt 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 (NMDA) glutamate receptors and is involved in glutamatergic neurotransmission. Our findings add to the growing evidence of genetic risk factors that act pleiotropically to increase risk for several neuropsychiatric disorders, including depression and suicide attempt, regardless of ancestry.