Genetic predisposition for meaningful health-domains of daily life such as peripheral muscle weakness and reduced functional capacity in patients with COPD is yet unknown. We aimed to find genetic variants associated with reduced functional status.

A cross-sectional study was conducted. Peripheral muscle strength was assessed with quadriceps maximum voluntary contraction and handgrip muscle strength. Functional capacity was determined using the six-minute walk test and the 1-minute sit-to-stand test. Hierarchical cluster analysis based on principal component analysis-transformed data of the 4 variables was conducted. A GWAS based on a logistic regression was performed, adjusted for age, sex, BMI, smoking status and FEV1pp.

209 people with COPD (67.9 7.9 years old; 21.2% female; FEV1pp 54.6 19.4) were included, of which 170 had genotyping data available. Three clusters have been found. Cluster 1 was characterized by patients of younger age, mostly male, less symptomatic, preserved muscle strength and functional capacity. Cluster 2 was characterised by a mild-to-moderate symptom burden, reduced muscle strength but preserved functional capacity. Cluster 3 was characterized by older patients, highly symptomatic, with a higher prevalence of women, peripheral muscle weakness and impaired functional capacity. We found 6 suggestive loci associated with cluster 3, that mapped to the genes GPC1, IQSEC1, PHACTR2, FAM177A1 and ANKRD11. FAM177A1 has been linked to myasthenic syndrome and hypotonia-cystinuria, conditions associated with muscle weakness and fatigability.

This study may help decoding the genetic architecture behind disease heterogeneity, creating avenues for personalised therapeutic approaches based on genetic background.