Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH) and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry, and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and we investigated the association between inbreeding, GBC, gallstone disease (GSD), and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROHabove 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions of FROHwith sex, age, and genetic risk of GSD that affected GBC risk. Specifically, the increase in GBC risk per 1% FROHwas 19% in men (p-value = 0.002), 30% in those under 60 years of age (p-value = 0.001), and 12% in those with a genetic risk of GSD above the median (p-value = 0.01). The present study highlighted the complex interplay between inbreeding, genetic ancestry, and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscored the importance of considering the population-specific genetic architecture, along with sex- and age-specific effects, when investigating the genetic basis of complex traits in Latin Americans.
拉丁美洲人群具有丰富的遗传背景，这导致其常染色体基因组纯合片段比例存在异质性，且美洲原住民血统的类型和比例各不相同。虽然自体纯合性已被证实与多种人类疾病相关，但关于拉丁美洲人群中近亲繁殖、遗传血统与癌症风险之间的关系，目前知之甚少。智利是全球胆囊癌发病率最高的国家之一，本研究通过对4029名遗传混合背景的智利人进行分析，探讨了近亲繁殖与胆囊癌、胆石症及体重指数之间的关联。我们计算了长度超过1.5 Mb的个体纯合片段比例以及加权多基因风险评分，并采用多元逻辑回归评估纯合性与胆囊癌风险之间的关联。研究发现，该人群中的纯合性是由遗传漂变和近亲繁殖共同作用形成的异质性混合结果。虽然未发现纯合性与总体胆囊癌风险存在关联，但我们检测到纯合片段比例与性别、年龄及胆石症遗传风险之间存在交互作用，这些因素共同影响胆囊癌风险。具体而言，纯合片段比例每增加1%，男性胆囊癌风险增加19%（p值=0.002），60岁以下人群风险增加30%（p值=0.001），胆石症遗传风险高于中位数者风险增加12%（p值=0.01）。本研究揭示了近亲繁殖、遗传血统和胆石症遗传风险在胆囊癌发生发展中的复杂相互作用。所采用的方法及研究结果强调，在探究拉丁美洲人群复杂性状的遗传基础时，必须综合考虑群体特异性遗传结构以及性别与年龄的特异性效应。
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