Deleterious Variants Contribute Minimal Excess Risk in Large-Scale Testing
Date Issued
2024-10-22
Author(s)
Yen-Tsung Huang
En-Yu Lai
Jia-Ying Su
Hsueh-Ju Lu
Yen-Lin Chen
Jer-Yuarn Wu
Chun-yu Wei
Ling-Hui Li
Cathy S.-J. Fann
Hsin-Chou Yang
Chien-Hsiun Chen
Hung-Hsin Chen
Yi-Min Liu
Ming-Fang Tsai
Erh-Chan Yeh
Chih-Kuang Cheng
Yen-Po Wang
Nai-Fang Chi
I-Cheng Lee
Harn-Shen Chen
Yun-Cheng Hsieh
Yi-Chu Liao
Shao-Jung Hsu
Shuo-Ming Ou
Kuan-Lin Lai
Chung-Chi Lin
Yi-Jen Chen
Peng-Hui Wang
Yung-Hung Luo
Yun-Ting Chang
Chih-Chiang Chen
Yu-Cheng Hsieh
Yi-Ming Chen
Tzu-Hung Hsiao
Ching-Heng Lin
Yen-Ju Chen
I-Chieh Chen
Chien-Lin Mao
Yen-Lin Chang
Shu-Jung Chang
Yi-Ju Liao
Chih-Hung Lai
Wei-Ju Lee
Hsin Tung
Ting-Ting Yen
Hsin-Chien Yen
Shy-Shin Chang
Yu-Sheng Chang
Ting-I Lee
Shauh-Der Yeh
Mei-Yi Wu
Ming-Shun Wu
Lung Wen Tsai
Cai-mei Zheng
Yu-Mei Chien
Yen-Hsu Chen
Cheng-Che E. Lan
Jeng-Hsien Yen
Wen-Chen Liang
Te-Fu Chan
Shyh-Shin Chiou
Shih-Chang Chuang
Shang-Jyh Hwang
Yi-Jung Lin
Yu-Chuang Huang
Wan-Ru Li
Tsai-Chuan Chen
Wei-Ting Huang
Kuan-Chih Chen
Shin-Yee Lim
Yi-Shiuan Shen
Chia-Chia Huang
Ya-Chung Tian
Chia-Ling Chen
Yao-Fan Fang
Ji-Tseng Fang
Yi-Hao Yen
Wei-Chi Wu
Wen-Shih Huang
Chi-Chin Sun
Tsung-Hua Yang
Shun-Fa Yang
Chia-Chuan Hsieh
Chih-Chien Sung
Feng-Chih Kuo
Shih-Hua Lin
Dueng-Yuan Hueng
Chien-Jung Lin
Hueng-Yuan Shen
Chang-Hsun Hsieh
Shinn-Zong Lin
Tso-Fu Wang
Tsung-Jung Ho
Pei-Wei Shueng
Chen-Hsi Hsieh
Kuo-Shyang Jeng
Gwo-Chin Ma
Ting-Yu Chang
Han-Sun Chiang
Yi-Tien Lin
Kuo-Jang Kao
Chen-Fang Hung
I-Mo Fang
Po-Yueh Chen
Kochung Tsui
Pui-Yan Kwok
Wei-Jen Yao
Shiou-Sheng Chen
Chih-Yang Huang
Da-Wei Wang
MING CHEN
Chun-houh Chen
Abstract
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.
Publisher
Cold Spring Harbor Laboratory
Type
preprint