MEPE loss-of-function variant associates with decreased bone mineral density and increased fracture risk

• DOI: 10.1038/s41467-020-17315-0
• Publication Date: 2020-10-23T09:03:23Z
• Authors: Ida Surakka; Lars G. Fritsche; Wei Zhou; Joshua Backman; Jack A. Kosmicki; Haocheng Lu; Ben Brumpton; Jonas B. Nielsen; Maiken E. Gabrielsen; Anne Heidi Skogholt; Brooke Wolford; Sarah E. Graham; Y. Eugene Chen; Seunggeun Lee; Hyun Min Kang; Arnulf Langhammer; Siri Forsmo; Bjørn O. Åsvold; Unnur Styrkarsdottir; Hilma Holm; Daniel Gudbjartsson; Kari Stefansson; Aris Baras; ; Xiaodong Bai; Suganthi Balasubr...; Leland Barnard; Andrew Blumenfeld; Michael Cantor; Giovanni Coppola; Aris Economides; Gisu Eom; Lukas Habegger; Young Hahn; Alicia Hawes; Marcus B. Jones; Shareef Khalid; Luca A. Lotta; Evan K. Maxwell; Lyndon J. Mitnaul; John D. Overton; Jeffrey G. Reid; Manuel Allen Reve...; William Salerno; Deepika Sharma; Alan Shuldiner; Jeffrey C. Staples; Ashish Yadav; Goncalo R. Abecasis; Kristian Hveem; Cristen J. Willer
• Keywords: Genome-wide Association Study; Minor allele frequency

A major challenge in genetic association studies is that most associated variants fall the non-coding part of human genome. We searched for with bone mineral density (BMD) after enriching discovery cohort loss-of-function (LoF) mutations by sequencing a subset Nord-Trøndelag Health Study, followed imputation remaining sample (N = 19,705), and identified ten known BMD loci. However, one previously unreported variant, LoF mutation MEPE, p.(Lys70IlefsTer26, minor allele frequency [MAF] 0.8%), was decreased ultradistal forearm (P-value 2.1 × 10-18), increased osteoporosis 4.2 10-5) fracture risk 1.6 10-5). The MEPE fractures further evaluated 279,435 UK (MAF 0.05%, heel estimated P-value 1.2 10-16, any 0.05) 375,984 Icelandic samples 0.03%, arm 0.12, 0.005). Screening before adulthood could potentially prevent due to lifelong effect on observed study. key implication precision medicine high-impact functional missing from publicly available cosmopolitan panels be clinically more relevant than polygenic scores.