%0 Journal Article %J Nat Commun %D 2021 %T Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. %A Jones, Garan %A Trajanoska, Katerina %A Santanasto, Adam J %A Stringa, Najada %A Kuo, Chia-Ling %A Atkins, Janice L %A Lewis, Joshua R %A Duong, ThuyVy %A Hong, Shengjun %A Biggs, Mary L %A Luan, Jian'an %A Sarnowski, Chloe %A Lunetta, Kathryn L %A Tanaka, Toshiko %A Wojczynski, Mary K %A Cvejkus, Ryan %A Nethander, Maria %A Ghasemi, Sahar %A Yang, Jingyun %A Zillikens, M Carola %A Walter, Stefan %A Sicinski, Kamil %A Kague, Erika %A Ackert-Bicknell, Cheryl L %A Arking, Dan E %A Windham, B Gwen %A Eric Boerwinkle %A Grove, Megan L %A Graff, Misa %A Spira, Dominik %A Demuth, Ilja %A van der Velde, Nathalie %A de Groot, Lisette C P G M %A Psaty, Bruce M %A Odden, Michelle C %A Fohner, Alison E %A Langenberg, Claudia %A Wareham, Nicholas J %A Bandinelli, Stefania %A van Schoor, Natasja M %A Huisman, Martijn %A Tan, Qihua %A Zmuda, Joseph %A Mellström, Dan %A Karlsson, Magnus %A Bennett, David A %A Buchman, Aron S %A De Jager, Philip L %A Uitterlinden, André G %A Völker, Uwe %A Kocher, Thomas %A Teumer, Alexander %A Rodriguéz-Mañas, Leocadio %A García, Francisco J %A Carnicero, José A %A Herd, Pamela %A Bertram, Lars %A Ohlsson, Claes %A Murabito, Joanne M %A Melzer, David %A Kuchel, George A %A Ferrucci, Luigi %A Karasik, David %A Rivadeneira, Fernando %A Kiel, Douglas P %A Pilling, Luke C %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Europe %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Growth Differentiation Factor 5 %K HLA-DQ alpha-Chains %K Humans %K Male %K Middle Aged %K Muscle Strength %K Muscle Weakness %K Polymorphism, Single Nucleotide %K Sarcopenia %X

Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.

%B Nat Commun %V 12 %P 654 %8 2021 Jan 28 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33510174?dopt=Abstract %R 10.1038/s41467-021-20918-w %0 Journal Article %J PLoS Genet %D 2019 %T Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations. %A Kowalski, Madeline H %A Qian, Huijun %A Hou, Ziyi %A Rosen, Jonathan D %A Tapia, Amanda L %A Shan, Yue %A Jain, Deepti %A Argos, Maria %A Arnett, Donna K %A Avery, Christy %A Barnes, Kathleen C %A Becker, Lewis C %A Bien, Stephanie A %A Bis, Joshua C %A Blangero, John %A Eric Boerwinkle %A Bowden, Donald W %A Buyske, Steve %A Cai, Jianwen %A Cho, Michael H %A Choi, Seung Hoan %A Choquet, Hélène %A Cupples, L Adrienne %A Cushman, Mary %A Daya, Michelle %A de Vries, Paul S %A Ellinor, Patrick T %A Faraday, Nauder %A Fornage, Myriam %A Gabriel, Stacey %A Ganesh, Santhi K %A Graff, Misa %A Gupta, Namrata %A He, Jiang %A Heckbert, Susan R %A Hidalgo, Bertha %A Hodonsky, Chani J %A Irvin, Marguerite R %A Johnson, Andrew D %A Jorgenson, Eric %A Kaplan, Robert %A Kardia, Sharon L R %A Kelly, Tanika N %A Kooperberg, Charles %A Lasky-Su, Jessica A %A Loos, Ruth J F %A Lubitz, Steven A %A Mathias, Rasika A %A McHugh, Caitlin P %A Montgomery, Courtney %A Moon, Jee-Young %A Morrison, Alanna C %A Palmer, Nicholette D %A Pankratz, Nathan %A Papanicolaou, George J %A Peralta, Juan M %A Peyser, Patricia A %A Rich, Stephen S %A Rotter, Jerome I %A Silverman, Edwin K %A Smith, Jennifer A %A Smith, Nicholas L %A Taylor, Kent D %A Thornton, Timothy A %A Tiwari, Hemant K %A Tracy, Russell P %A Wang, Tao %A Weiss, Scott T %A Weng, Lu-Chen %A Wiggins, Kerri L %A Wilson, James G %A Yanek, Lisa R %A Zöllner, Sebastian %A North, Kari E %A Auer, Paul L %A Raffield, Laura M %A Reiner, Alexander P %A Li, Yun %K Adult %K Aged %K Aged, 80 and over %K beta-Globins %K Black or African American %K Computational Biology %K Databases, Genetic %K Female %K Gene Frequency %K Genetic Predisposition to Disease %K Genetics, Population %K Genome-Wide Association Study %K Genotyping Techniques %K Hispanic or Latino %K Humans %K Linkage Disequilibrium %K Male %K Middle Aged %K Precision Medicine %K United States %K Whole Genome Sequencing %X

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.

%B PLoS Genet %V 15 %P e1008500 %8 2019 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/31869403?dopt=Abstract %R 10.1371/journal.pgen.1008500