男性低睾酮水平的遗传易感性及其生物学和筛查意义：来自英国生物银行的数据。
Genetic Susceptibility for Low Testosterone in Men and Its Implications in Biology and Screening: Data from the UK Biobank.
作者信息
Fantus Richard J, Na Rong, Wei Jun, Shi Zhuqing, Resurreccion W Kyle, Halpern Joshua A, Franco Omar, Hayward Simon W, Isaacs William B, Zheng S Lilly, Xu Jianfeng, Helfand Brian T
机构信息
Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
出版信息
Eur Urol Open Sci. 2021 May 25;29:36-46. doi: 10.1016/j.euros.2021.04.010. eCollection 2021 Jul.
BACKGROUND
Despite strong evidence of heritability, few studies have attempted to unveil the genetic underpinnings of testosterone levels.
OBJECTIVE
To identify testosterone-associated loci in a large study and assess their biological and clinical implications.
DESIGN SETTING AND PARTICIPANTS
The participants were men from the UK Biobank. A two-stage genome-wide association study (GWAS) was first used to identify/validate loci for low testosterone (LowT, <8 nmol/l) in 80% of men ( = 148 902). The cumulative effect of independent LowT risk loci was then evaluated in the remaining 20% of men.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Associations of single nucleotide polymorphisms (SNPs) with LowT were tested using an additive model. Analyses of the expression quantitative trait loci (eQTLs) were performed to assess the associations between significant SNPs and expression of nearby genes (within 1 Mbp). A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent SNPs on LowT risk.
RESULTS AND LIMITATIONS
The two-stage GWAS found SNPs in 141 loci of 41 cytobands that were significantly associated with LowT ( < 5 × 10), including 94 novel loci from 38 cytobands. An eQTL analysis of these 141 loci revealed significant associations with RNA expression of 155 genes, including previously implicated ( and ) and novel (, , and ) genes. Among the 141 loci, 42 were independently associated with LowT after a multivariable analysis. The GRS based on these 42 loci was significantly associated with LowT risk in independent individuals ( = 37 225, = 3.16 × 10). The risk ratio for LowT between men in the top and those in the bottom GRS deciles was 4.98-fold. Results are limited in generalizability as only Caucasians were studied.
CONCLUSIONS
Identification of the genetic variants associated with LowT may improve our understanding of its etiology and identify high-risk men for LowT screening.
PATIENT SUMMARY
We identified 141 new genetic loci that can be incorporated into a genetic risk score that can potentially identify men with low testosterone.
背景
尽管有强有力的遗传证据，但很少有研究试图揭示睾酮水平的遗传基础。
目的
在一项大型研究中识别与睾酮相关的基因座，并评估其生物学和临床意义。
设计、地点和参与者：参与者为来自英国生物银行的男性。首先采用两阶段全基因组关联研究（GWAS）在80%的男性（n = 148902）中识别/验证低睾酮（LowT，<8 nmol/l）的基因座。然后在其余20%的男性中评估独立的LowT风险基因座的累积效应。
结局测量和统计分析
使用加性模型测试单核苷酸多态性（SNP）与LowT的关联。进行表达定量性状基因座（eQTL）分析，以评估显著SNP与附近基因（1 Mbp内）表达之间的关联。使用遗传风险评分（GRS）评估多个独立SNP对LowT风险的累积效应。
结果与局限性
两阶段GWAS在41个细胞带的141个基因座中发现了与LowT显著相关的SNP（P < 5×10⁻⁸），包括来自38个细胞带的94个新基因座。对这141个基因座的eQTL分析揭示了与155个基因的RNA表达存在显著关联，包括先前涉及的（和）以及新的（、和）基因。在这141个基因座中，42个在多变量分析后与LowT独立相关。基于这42个基因座的GRS与独立个体中的LowT风险显著相关（n = 37225，P = 3.16×10⁻⁴）。GRS十分位数最高和最低的男性之间LowT的风险比为4.98倍。由于仅研究了高加索人，结果的普遍性有限。
结论
识别与LowT相关的基因变异可能会增进我们对其病因的理解，并识别出进行LowT筛查的高危男性。
患者总结
我们识别出141个新的基因座，可纳入遗传风险评分，该评分可能识别出睾酮水平低的男性。
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