Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality?
Genetic determinants of mortality. Can findings from genome-wide association studies explain variation in human mortality?
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DOI：
10.1007/s00439-013-1267-6
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发表时间：
2013-05-01
期刊：
影响因子：
5.3
通讯作者：
Tiemeier, Henning
中科院分区：
文献类型：
--
作者：
Ganna, Andrea;Rivadeneira, Fernando;Tiemeier, Henning
双胞胎研究估计长寿的遗传率约为20- 30%。全基因组关联研究（GWAS）已经揭示了大量的发病率的决定因素，但到目前为止，还没有发现新的多态性与长寿本身在GWAS。我们的目的是确定死亡率的遗传结构是否可以用与死亡率相关的常见性状和疾病相关的单核苷酸多态性（SNP）来解释。通过对已发表的GWAS进行广泛的质量控制，我们从与125种疾病或与总体死亡率相关的风险因素相关的707个常见SNP中创建了一个遗传评分。我们前瞻性研究了遗传评分与以下因素的相关性：（1）死亡时间;（2）在荷兰和瑞典两个基于人群的队列中（N = 15，039;年龄范围47-99岁），9种主要疾病（冠心病、中风、心力衰竭、糖尿病、痴呆、肺癌、乳腺癌、结肠癌和前列腺癌）中第一种疾病的发病率。在中位随访6.3年（最长22.2年）期间，我们观察到4，318例死亡和2，132例疾病事件。遗传评分与至死亡时间显著相关[每个增加的风险等位基因的风险比（HR）= 1.003，P值= 0.006; HR第四与第一四分位数= 1.103]。遗传评分与主要疾病发病率之间的关联更强（HR/增加的风险等位基因= 1.004，P值= 0.002; HR第四与第一四分位数= 1.160）。与老年死亡的个体相关性更强。我们的研究结果与死亡率作为一个复杂的和高度多基因的性状，不容易解释的常见的遗传变异相关的疾病和生理特征的观点是一致的。
Twin studies have estimated the heritability of longevity to be approximately 20-30 %. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS. We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years). During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death [hazard ratio (HR) per added risk allele = 1.003, P value = 0.006; HR 4th vs. 1st quartile = 1.103]. The association between the genetic score and incidence of major diseases was stronger (HR per added risk allele = 1.004, P value = 0.002; HR 4th vs. 1st quartile = 1.160). Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.