Multi-trait Genome-Wide Analysis Identified 20 Novel Loci for Sarcopenia-Related Traits in UK Biobank.

Abstract

This study aims to identify novel loci associated with sarcopenia-related traits in UK Biobank (UKB) through multi-trait genome-wide analysis. To identify novel loci associated with sarcopenia, we integrated the genome-wide association studies (GWAS) of usual walking pace (UWP) and hand grip strength (HGS) to conduct a joint association study known as multi-trait analysis of GWAS (MTAG). We performed a transcriptome-wide association study (TWAS) to analyze the results of MTAG in relation to mRNA expression data for genes identified in skeletal muscle. Additionally, we utilized Weighted Gene Co-Expression Network Analysis (WGCNA) and Protein-Protein Interaction (PPI) networks to explore the relationships between the identified genes and hub genes related to sarcopenia. We identified 15 novel loci associated with UWP and 5 novel loci associated with HGS at the genome wide significance level (GWS, <math xmlns="http://www.w3.org/1998/Math/MathML"><mrow><mi>p</mi> <mo><</mo> <mn>5</mn> <mo>×</mo> <msup><mrow><mn>10</mn></mrow> <mrow><mo>-</mo> <mn>8</mn></mrow> </msup> </mrow> </math> ). After TWAS ( <math xmlns="http://www.w3.org/1998/Math/MathML"> <mrow><msub><mi>p</mi> <mrow><mi>TWAS</mi></mrow> </msub> <mo><</mo> <mn>6.659</mn> <mo>×</mo> <msup><mrow><mn>10</mn></mrow> <mrow><mo>-</mo> <mn>6</mn></mrow> </msup> <mo>,</mo> <mn>0.05</mn> <mo>/</mo> <mn>7509</mn></mrow> </math> ), we found two significant genes: PPP1R3A, located at 7q31.1 and associated with HGS, and ZBTB38, located at 3q23 and associated with UWP. 11 identified genes associated with hub genes for sarcopenia were obtained through WGCNA. Our findings offer new insights into biological mechanisms underlying sarcopenia and identify several novel genes related to sarcopenia that warrant in-depth study.