Genome-wide association study of proteomic aging reveals shared genetic architectures with longevity, early life development, and age related diseases
Argentieri, M. A.; Loughnan, R.; Wang, Y.; Liao, C.; Wang, B.; Cheng, W.; Ye, R.; Ivankovic, F.; Amin, N.; Yu, C.; Lv, J.; Li, L.; Wright, N.; Fan, C. C.; Palotie, A.; Bennett, D.; Chen, Z.; Alvergne, A.; van Duijn, C. M.; Neale, B. M.; Daly, M. J.
Show abstract
There is still relatively little known about the genetic underpinnings of proteomic aging clocks. Here, we describe a genome-wide association study of proteomic aging in the UK Biobank (n=38,865), identifying 27 loci associated with participants proteomic age gap (ProtAgeGap). ProtAgeGap exhibits a strong genetic correlation with longevity (rg = -0.83), and in FinnGen a ProtAgeGap polygenic score (PGS) was associated with significantly increased odds of achieving longevity (n=500,348; OR = 1.43). Additional PGS analyses in All of Us (n=117,415), China Kadoorie Biobank (n=100,640), and ABCD Study (n=5,204) demonstrate reproducible associations across biobanks of ProtAgeGap PGS with obesity, cardiometabolic disease, and osteoarthritis in adults, and with developmental timing in children. Finally, colocalization analysis identified FTO as an obesity-related mechanism uniting diverse aging traits. Our results demonstrate a shared genetic architecture across the life course of ProtAgeGap with longevity, early developmental biology, and cardiometabolic and musculoskeletal diseases.
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