Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in European Populations
Nonsynonymous Variation in NKPD1 Increases Depressive Symptoms in European Populations
复制标题
DOI：
10.1016/j.biopsych.2016.08.008
复制
发表时间：
2017-04-15
影响因子：
10.6
通讯作者：
van Duijn, Cornelia M.
中科院分区：
文献类型：
--
作者：
Amin, Najaf;Belonogova, Nadezhda M.;van Duijn, Cornelia M.
背景技术背景：尽管遗传力高，很少成功的抑郁症相关性状的遗传决定因素的映射通过全基因组关联studies.METHODS：为了确定与抑郁症相关的基因，我们进行了一个基于基因的关联分析非同义变异捕获使用外显子组测序和外显子组芯片基因分型的遗传隔离的人口从荷兰（n = 1999）。最后，我们在一个独立的基于人群的队列（n 5 1604）中再现了我们的显著发现：我们检测到抑郁症状与基因NKPD 1显著相关（p = 3.7*102（-08））。在发现研究中，该基因的非同义变异解释了0.9%的性别和年龄调整后的抑郁症状方差，转化为总估计遗传力的3.8%（h（2）= 0.24）。在独立复制样本中也观察到抑郁症状与NKPD 1的显著关联（n = 1604; p = 1.5 * 10（-03）），尽管在NKPD 1基因中观察到的非同义遗传变异组中与发现队列几乎没有重叠。发现和复制研究的荟萃分析提高了关联信号（p = 1.0 * 10（-09））。结论：我们的研究表明，基因NKPD 1的非同义变异影响一般人群的抑郁症状。NKPD 1被预测参与鞘脂的从头合成，这与抑郁症的发病机制有关。
BACKGROUND: Despite high heritability, little success was achieved in mapping genetic determinants of depression-related traits by means of genome-wide association studies.METHODS: To identify genes associated with depressive symptomology, we performed a gene-based association analysis of nonsynonymous variation captured using exome-sequencing and exome-chip genotyping in a genetically isolated population from the Netherlands (n = 1999). Finally, we reproduced our significant findings in an independent population-based cohort ( n 5 1604).RESULTS: We detected significant association of depressive symptoms with a gene NKPD1 (p = 3.7*102(-08)). Nonsynonymous variants in the gene explained 0.9% of sex-and age-adjusted variance of depressive symptoms in the discovery study, which is translated into 3.8% of the total estimated heritability (h(2) = 0.24). Significant association of depressive symptoms with NKPD1 was also observed ( n = 1604; p = 1.5 * 10(-03)) in the independent replication sample despite little overlap with the discovery cohort in the set of nonsynonymous genetic variants observed in the NKPD1 gene. Meta-analysis of the discovery and replication studies improved the association signal (p = 1.0 * 10(-09)).CONCLUSIONS: Our study suggests that nonsynonymous variation in the gene NKPD1 affects depressive symptoms in the general population. NKPD1 is predicted to be involved in the de novo synthesis of sphingolipids, which have been implicated in the pathogenesis of depression.