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

BACKGROUND

Multimorbidity, the presence of two or more conditions in one person, is common but studies are often limited to observational data and single datasets. We address this gap by integrating large-scale primary-care and genetic data from multiple studies to interrogate multimorbidity patterns and producing digital resources to support future research.

METHODS

We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large primary-care 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 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 databases, and up to three sources of genetic data, for each pair of conditions. We classified pairs of conditions as across or within-domain based on the international classification of disease.

FINDINGS: We identified 72 chronic conditions, with 43.6% of 2546 pairs showing higher co-occurrence than chance in primary care and evidence of shared genetics. Many across-domain pairs exhibited substantial shared genetics (e.g., iron deficiency anaemia and peripheral arterial disease: genetic correlation Rg = 0.45 [95% Confidence Intervals 0.27:0.64]). 33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (Rg = -0.14 [-0.21:-0.06]), due to potential adverse drug effects. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred in primary care 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 together in primary care but were positively genetically correlated (OR = 0.84 [0.75:0.94], Rg = 0.20 [0.11:0.29]).

INTERPRETATION: Most pairs of chronic conditions show evidence of shared genetics, and co-occurrence in primary care, suggesting shared mechanisms. The identified patterns of shared genetics, negative correlations and discordance between genetic and observational data provide a foundation for future multimorbidity research.

FUNDING: UK Medical Research Council [MR/W014548/1].