Yen-Tsung HuangEn-Yu LaiJia-Ying SuHsueh-Ju LuYen-Lin ChenJer-Yuarn WuChun-yu WeiLing-Hui LiCathy S.-J. FannHsin-Chou YangChien-Hsiun ChenHung-Hsin ChenYi-Min LiuMing-Fang TsaiErh-Chan YehChih-Kuang ChengYen-Po WangNai-Fang ChiI-Cheng LeeHarn-Shen ChenYun-Cheng HsiehYi-Chu LiaoShao-Jung HsuShuo-Ming OuKuan-Lin LaiChung-Chi LinYi-Jen ChenCHIA-MING CHANGPeng-Hui WangYung-Hung LuoYun-Ting ChangChih-Chiang ChenYu-Cheng HsiehYi-Ming ChenTzu-Hung HsiaoChing-Heng LinYen-Ju ChenI-Chieh ChenChien-Lin MaoYen-Lin ChangShu-Jung ChangYi-Ju LiaoChih-Hung LaiWei-Ju LeeHsin TungTing-Ting YenHsin-Chien YenShy-Shin ChangYu-Sheng ChangTing-I LeeShauh-Der YehMei-Yi WuMing-Shun WuLung Wen TsaiCai-mei ZhengYu-Mei ChienYen-Hsu ChenCheng-Che E. LanJeng-Hsien YenTSUNG-HSIEN LINWen-Chen LiangTe-Fu ChanShyh-Shin ChiouShih-Chang ChuangShang-Jyh HwangYi-Jung LinYu-Chuang HuangWan-Ru LiTsai-Chuan ChenWei-Ting HuangKuan-Chih ChenShin-Yee LimYi-Shiuan ShenChia-Chia HuangYa-Chung TianCHIEN-HUNG CHENChia-Ling ChenYao-Fan FangJi-Tseng FangYi-Hao YenWei-Chi WuWen-Shih HuangChi-Chin SunMEI-JYH CHENCHING-HUNG LINTsung-Hua YangShun-Fa YangChia-Chuan HsiehTSEN-FANG TSAITUNG-HUNG SUJYH-MING LIOUPEI-LIN LEEMING-YANG WANGChih-Chien SungFeng-Chih KuoShih-Hua LinDueng-Yuan HuengChien-Jung LinHueng-Yuan ShenChang-Hsun HsiehShinn-Zong LinTso-Fu WangTsung-Jung HoPei-Wei ShuengChen-Hsi HsiehKuo-Shyang JengGwo-Chin MaTing-Yu ChangHan-Sun ChiangYi-Tien LinKuo-Jang KaoChen-Fang HungI-Mo FangPo-Yueh ChenKochung TsuiPui-Yan KwokWei-Jen YaoShiou-Sheng ChenChih-Yang HuangDa-Wei WangMING CHENChun-houh Chen2024-11-202024-11-202024-10-22https://scholars.lib.ntu.edu.tw/handle/123456789/723159<jats:title>Abstract</jats:title><jats:p>DNA sequencing of patients with rare disorders has been highly successful in identifying “causal variants” for numerous conditions. However, there are many reports of healthy individuals who harbor these deleterious variants, leading to the concept of incomplete penetrance and doubt about the utility of genetic testing in clinical practice and population screening. As the deleterious variants are rare, the penetrance of these variants in the population is largely unknown. We analyzed the genetic and clinical data from 486,956 participants of the Taiwan Precision Medicine Initiative (TPMI) to determine the risk difference between those with and without deleterious variants. In all, we analyzed 292 disease-relevant variants and their clinical outcomes to assess their association. We found that only 15 variants show a risk difference exceeding 5% between those with or without the variants. In essence, 87.3% of deleterious variants exhibit minimal risk differences, suggesting a limited impact on the individual and population levels. Our analysis revealed increasing trends with age in six cardiovascular and degenerative diseases and bell-shaped trends in two cancers. Additionally, we identified three clinical outcomes exhibiting a dose-response relationship with the number of deleterious variants. Our findings show that large-scale testing of deleterious variants found in the literature is not warranted, except for those exhibiting large disease risk differences.</jats:p>enpreprinthttps://doi.org/10.1101/2024.10.21.24315653