The UK Biobank is a prospective study of more than 500 000 participants that has aggregated data from questionnaires, physical measures, biomarkers, imaging and follow-up for a wide range of health-related outcomes, together with genome-wide genotyping supplemented with high-density imputation. Previous studies have highlighted fine-scale population structure in the UK on a North-West to South-East cline, but the impact of unmeasured geographical confounding on genome-wide association studies (GWAS) of complex human traits in the UK Biobank has not been investigated. We considered 368 325 white British individuals from the UK Biobank, and performed GWAS of their birth location. We demonstrate that widely used approaches to adjust for population structure, including principal components analysis and mixed modelling with a random effect for a genetic relationship matrix, cannot fully account for the fine-scale geographical confounding in the UK Biobank. We observe significant genetic correlation of birth location with a range of lifestyle-related traits, including body-mass index and fat mass, hypertension, and lung function, even after adjustment for population structure. Variants driving associations with birth location are also strongly associated with many of these lifestyle-related traits after correction for population structure, indicating that there could be environmental factors that are confounded with geography that have not been adequately accounted for. Our findings highlight the need for caution in the interpretation of lifestyle-related trait GWAS in UK Biobank, particularly in loci demonstrating strong residual association with birth location.

中文翻译：

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英国生物银行的精细种群结构：对全基因组关联研究的影响。

英国生物银行是一项对超过 500,000 名参与者进行的前瞻性研究，该研究从问卷、物理测量、生物标志物、成像和随访中收集了广泛的健康相关结果的数据，以及全基因组基因分型，并辅以高密度插补。以前的研究强调了英国西北到东南部的精细人口结构，但未测量的地理混杂对英国生物银行中复杂人类特征的全基因组关联研究 (GWAS) 的影响尚未得到证实。调查。我们考虑了来自英国生物银行的 368 325 名英国白人个体，并对他们的出生地点进行了 GWAS。我们证明了广泛使用的调整人口结构的方法，包括主成分分析和对遗传关系矩阵具有随机效应的混合建模，不能完全解释英国生物银行中精细尺度的地理混杂。我们观察到出生地点与一系列生活方式相关特征的显着遗传相关性，包括体重指数和脂肪量、高血压和肺功能，即使在调整人口结构后也是如此。在校正人口结构后，与出生地点相关的变异也与许多与生活方式相关的特征密切相关，这表明可能存在与地理混淆的环境因素尚未得到充分考虑。我们的研究结果强调了在解释英国生物银行生活方式相关性状 GWAS 时需要谨慎，