Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

中文翻译：

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在西班牙裔/拉丁美洲裔人群中祖先对2型糖尿病遗传风险推断的影响。

西班牙裔/拉丁美洲裔（HL）人群承担的2型糖尿病（T2D）负担过高。使用多基因风险评分（PRS）预测T2D遗传风险的能力为改善筛查和预防提供了广阔前景。但是，在具有不同血统特征的HL人群中准确推断遗传风险存在许多并发症。我们调查了祖先如何使用PRS在来自哥伦比亚和美国（美国）的不同HL人群中影响T2D遗传风险的推断。在哥伦比亚，我们比较了Antioquia的Mestizo人群和Chocó的非裔哥伦比亚人群的T2D遗传风险，在美国，我们比较了欧洲裔美国人和墨西哥裔美国人。来自1000个基因组计划和ChocoGen研究计划的全基因组序列和基因型用于遗传血统推断和T2D多基因风险评分（PRS）计算。通过与非洲，欧洲和美洲原住民参考基因组进行比较，推断出HL基因组的大陆祖先分数，并使用从对不同祖先的队列进行的多个全基因组关联研究（GWAS）中获得的T2D风险变体来计算PRS。根据祖先对衍生等位基因的频率，对T2D风险推断中的祖先偏差进行了校正，并将其应用于此处研究的HL人群的PRS计算中。哥伦比亚和美国HL人群的T2D遗传风险与非洲和美洲原住民血统呈正相关，与欧洲血统负相关。Chocó的非洲裔哥伦比亚人的预测T2D风险高于安蒂奥基亚（Antioquia），墨西哥裔美国人的预测风险高于欧洲裔美国人。推断出的T2D相对风险对用于变体发现的GWAS队列的祖先差异具有鲁棒性。对于跨种族的GWAS，特定人群的变体和在整个人群中具有相同方向效应的变体产生一致的结果。尽管如此，对T2D风险预测中偏倚的控制证实了对遗传血统的明确考虑可以产生更可靠的跨群体遗传风险推断。在人群之间复制的T2D关联提供了更可靠的风险推断，对特定人群的祖先和衍生风险等位基因频率进行建模可以帮助控制PRS估计中的偏差。