A systematic analysis of the contribution of genetics to multimorbidity and comparisons with primary care data

Abstract

AbstractBackgroundMultimorbidity, the presence of two or more conditions in one person, is increasingly prevalent. Yet shared biological mechanisms of specific pairs of conditions often remain poorly understood. We address this gap by integrating large-scale primary care and genetic data to elucidate potential causes of multimorbidity.MethodsWe defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large representative healthcare databases [CPRD (UK) N=2,425,014 and SIDIAP (Spain) N=1,053,640], and estimated heritability using the same definitions in UK Biobank (N=451,197). We used logistic regression models to estimate the co-occurrence of pairs of conditions in the primary care data.Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across healthcare databases, and up to three sources of genetic data, for each condition pair. We classified pairs of conditions as across or within-domain based on the international classification of disease.FindingsWe identified N=72 chronic conditions, with 43·6% of 2546 pairs showing higher co-occurrence than expected and evidence of shared genetics. Notably, across-domain pairs like iron deficiency anaemia and peripheral arterial disease exhibited substantial shared genetics (genetic correlationRg=0·45[95% Confidence Intervals 0·27:0·64]). N=33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (Rg=-0·14[-0·21:-0·06]), indicating potential protective mechanisms. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred but were not genetically correlated (Odds-Ratio=2·23[2·09:2·37],Rg=0·04[-0·20:0·28]) and schizophrenia and fibromyalgia were less likely to co-occur but were positively genetically correlated (OR=0·84[0·75:0·94],Rg=0·20[0·11:0·29]).InterpretationMost pairs of chronic conditions show evidence of shared genetics and co-occurrence in primary care, suggesting shared mechanisms. The identified shared mechanisms, negative correlations and discordance between genetic and observational data provide a foundation for future research on prevention and treatment of multimorbidity.FundingUK Medical Research Council [MR/W014548/1].