Deleterious Variants Contribute Minimal Excess Risk in Large-Scale Testing
Authors: Huang Yen-Tsung , Lai En-Yu , Su Jia-Ying , Lu Hsueh-Ju , Chen Yen-Lin , Wu Jer-Yuarn , Wei Chun-yu , Li Ling-Hui , Fann Cathy S.-J. , Yang Hsin-Chou , Chen Chien-Hsiun , Chen Hung-Hsin , Liu Yi-Min , Tsai Ming-Fang , Yeh Erh-Chan , Cheng Chih-Kuang , Wang Yen-Po , Chi Nai-Fang , Lee I-Cheng , Chen Harn-Shen , Hsieh Yun-Cheng , Liao Yi-Chu , Hsu Shao-Jung , Ou Shuo-Ming , Lai Kuan-Lin , Lin Chung-Chi , Chen Yi-Jen , Chang Chia-Ming , Wang Peng-Hui , Luo Yung-Hung , Chang Yun-Ting , Chen Chih-Chiang , Hsieh Yu-Cheng , Chen Yi-Ming , Hsiao Tzu-Hung , Lin Ching-Heng , Chen Yen-Ju , Chen I-Chieh , Mao Chien-Lin , Chang Shu-Jung , Chang Yen-Lin , Liao Yi-Ju , Lai Chih-Hung , Lee Wei-Ju , Tung Hsin , Yen Ting-Ting , Yen Hsin-Chien , Chang Shy-Shin , Chang Yu-Sheng , Lee Ting-I , Yeh Shauh-Der , Wu Mei-Yi , Wu Ming-Shun , Tsai Lung Wen , Zheng Cai-mei , Chien Yu-Mei , Lin Tsung-Hsien , Chen Yen-Hsu , Lan Cheng-Che E. , Yen Jeng-Hsien , Liang Wen-Chen , Chan Te-Fu , Chiou Shyh-Shin , Chuang Shih-Chang , Hwang Shang-Jyh , Lin Yi-Jung , Huang Yu-Chuang , Li Wan-Ru , Chen Tsai-Chuan , Huang Wei-Ting , Chen Kuan-Chih , Lim Shin-Yee , Shen Yi-Shiuan , Huang Chia-Chia , Chen Chien-Hung , Tian Ya-Chung , Chen Chia-Ling , Fang Yao-Fan , Fang Ji-Tseng , Yen Yi-Hao , Wu Wei-Chi , Huang Wen-Shih , Sun Chi-Chin , Chen Mei-Jyh , Lin Ching-Hung , Yang Tsung-Hua , Lee Pei-Lin , Wang Ming-Yang , Tsai Tsen-Fang , Su Tung-Hung , Liou Jyh-Ming , Yang Shun-Fa , Hsieh Chia-Chuan , Sung Chih-Chien , Kuo Feng-Chih , Lin Shih-Hua , Hueng Dueng-Yuan , Lin Chien-Jung , Shen Hueng-Yuan , Hsieh Chang-Hsun , Lin Shinn-Zong , Wang Tso-Fu , Ho Tsung-Jung , Shueng Pei-Wei , Hsieh Chen-Hsi , Jeng Kuo-Shyang , Ma Gwo-Chin , Chang Ting-Yu , Chiang Han-Sun , Lin Yi-Tien , Kao Kuo-Jang , Hung Chen-Fang , Fang I-Mo , Chen Po-Yueh , Tsui Kochung , Kwok Pui-Yan , Yao Wei-Jen , Chen Shiou-Sheng , Chen Ming , Huang Chih-Yang , Wang Da-Wei , Chen Chun-houh 
Published: October 2024

AbstractDNA 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.