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

Journal article

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.

Authors: Murrin, O; Mounier, N; Voller, B; Tata, L; Gallego-Moll, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: EBioMedicine
• Volume: 113
• Article number: 105584
• Publication date: 2025-02-06
• Acceptance date: 2025-01-20
• DOI: 10.1016/j.ebiom.2025.105584
• EISSN: 2352-3964
• Language: English
• Keywords: chronic disease; multiple long-term conditions; comorbidity; observational; genotype