台灣人口中多基因遺傳對複雜性疾病之負擔與終身風險的影響

Abstract

全基因組關聯研究揭示了常見基因變異在複雜疾病中的顯著作用。多基因風險分數透過加總多個基因變異的效應來估計個體對疾病的遺傳易感性，已成為預測疾病風險和制定個性化預防和治療策略的有用工具。先前的多基因風險分數研究主要關注疾病的相對風險，而針對個體層面的絕對風險和遺傳風險因素對疾病負擔的分析在非歐洲人群中尤其有限，而這些對評估風險和指導公共衛生干預非常有幫助。因此，本研究旨在量化遺傳因子對台灣常見疾病的終身風險和疾病負擔的貢獻程度。 利用台灣人體生物資料庫和2019年全球疾病負擔研究的數據，我們選出三種在台灣具有顯著負擔的常見疾病，包含第二型糖尿病、高血壓以及消化性潰瘍。我們使用PRS-CSx計算每種疾病的多基因風險評分，通過Cox比例風險模型估計多基因風險分數對疾病的影響。接著，我們利用遺傳效應和2019年全球疾病負擔研究的估計值，計算出多基因風險分數對疾病絕對風險和疾病負擔的貢獻，並以傷殘調整生命年作為疾病負擔的衡量方法。此外，我們亦比較了遺傳因素與這些疾病的常見風險因素對疾病負擔的貢獻程度，以更好地理解遺傳的相對重要性。 我們的研究結果顯示，遺傳風險因素對此三種疾病之風險有顯著的效應，並在性別、年齡和家庭史上存在差異。對於第二型糖尿病和高血壓，多基因風險分數高(前10%)之於低(後90%)的相對效應為男性小於女性，而消化性潰瘍則相反。隨著年齡的增加，多基因風險分數的效應會減弱，而比起具有家族史的人群，遺傳效應在不具家庭史的組別來得更高。將相對風險轉換成疾病絕對風險則顯示，對於第二型糖尿病，介於30至40歲且多基因風險分數在前10%的人在約40歲時就可達到45歲的篩檢閾值，而女性的估計值大於男性；對於高血壓，30至40歲且多基因風險評分在前10%的人在65至70歲時的發病率比多基因風險分數在後10%的人高出8.22倍，此估計值則男性略高於女性；對於消化性潰瘍，介於30至40歲且多基因風險評分在前10%的人在約57歲時達到建議的篩檢閾值。最後，我們計算了高多基因風險分數的可歸因傷殘調整生命年，結果顯示，前10%第二型糖尿病的多基因風險分數可導致1.61年的健康壽命損失，此效應和高身體質量指數對疾病負擔的貢獻相當；而高血壓之相對應數值為0.22年，和高度飲酒的影響相似；消化性潰瘍的遺傳影響相較可改變風險因素則較低。 通過基於個體化基因特徵的分層風險和負擔估計，這些發現突顯了遺傳風險因素對常見疾病的重要性，可能有助於制定針對台灣人群的個人化疾病干預和預防策略。

Genome-wide association studies have revealed a significant role of common genetic variations in common complex disorders. Polygenic risk score (PRS), which aggregates the effects of many genetic variants to estimate an individual's genetic predisposition to a disease, has been developed as a useful tool to predict disease risk and inform personalized prevention and treatment strategies. Previous studies of PRS have mostly examined relative risks on disease, while analyses of absolute risk and burden of disease attributable to genetic risk factors at the individual level—both informative for evaluating risk and guiding public health interventions—have been limited, particularly in non-European populations. This study aims to quantify the degree of genetic contribution to lifetime risk and disease burden for selected common diseases in Taiwan. Leveraging data in the Taiwan Biobank and the 2019 Global Burden of Disease (GBD) study, we identified three common diseases in Taiwan with nontrivial burden as measured in disability-adjusted life years (DALYs), including type 2 diabetes (T2D), hypertension, and peptic ulcer disease (PUD). We calculated polygenic risk scores (PRS) for each disease with PRS-CSx and estimated the effect of PRS on disease in hazard ratios via Cox proportional hazards models. We then transformed the genetic effects into its contribution to absolute risk and individual DALYs, using estimates derived from the 2019 GBD study. Additionally, we compared the burden of genetic factors with those from common risk factors of the diseases to better understand the relative importance of genetics. Our findings demonstrated a prominent effect of genetic risk factors on the three diseases, with variations observed across sex, age, and family history. Comparing those in the top 10% PRS to the bottom 90%, the relative risk of disease was smaller in males than in females for T2D and hypertension, while the opposite was true for PUD. These effects declined when age increased and were higher in those without than with family history. Transforming relative risk to absolute risk, for T2D, individuals in the top 10% PRS could reach the screening threshold of cumulative incidence for a 45-year-old by age 40, and the risk was higher in females than in males; for hypertension, those aged 30-40 in the top 10% PRS had 8.22 times higher incidence at ages 65-70 than those in the bottom 90%, slightly larger for males than in females; for PUD, individuals in the top 10% PRS could reach the threshold for a 60-year-old by around 57-year-old. Estimation of individual DALYs suggested that the top 10% PRS for T2D contributed to a 1.61-year loss of healthy life years, similar to that attributable to high BMI, while for hypertension, it was 0.22 years, akin to high alcohol use. The genetic impact on peptic ulcer disease (PUD) was comparatively low relative to modifiable risk factors. By providing stratified risk and burden estimates given individualized genetic profiles, these findings highlight the importance of genetic risk factors to common diseases that may inform tailored disease intervention and prevention strategies in the Taiwanese population.