Identifying genetic variants causal for multiple long-term conditions: informing opportunities for intervention and prevention

Multiple long-term conditions (MLTC), the coexistence of two or more long-term conditions (LTCs) in an individual, is an increasingly prevalent and complex clinical challenge. We aimed to uncover opportunities for therapeutic intervention in MLTC and highlight potential adverse effects using genetics to identify shared biological pathways across conditions. Across 72 heritable LTCs common in adults aged [≥]65, we analysed genome-wide association study (GWAS) summary statistics from meta-analyses incorporating up to three data sources (UK Biobank, FinnGen, and condition-specific consortia) from genetically European-ancestry participants. Across 843 condition pairs sharing genome-wide significant variants, we performed statistical colocalisation to identify shared causal genetic variants. Variants showing evidence of causality for [≥]3 LTCs were prioritised for investigation of likely causal genes, biological pathways, and druggability. Findings were replicated in Our Future Health (OFH, N=550,000). Colocalisation analyses identified 281 genetic variants causal for specific LTC pairs and 85 variants causal for [≥]3 LTCs. These 85 variants were located in 34 genomic regions with strong evidence of shared causality across multiple conditions. Thirteen of the 34 regions fully replicated in OFH, with others having partial replication. Eight variants showed concordant directions of effects across conditions, suggesting potential opportunities for drug development; results include a variant in GDF7 causal for diverticular disease, gastro-oesophageal reflux disease, and prostate cancer, suggesting multisystemic mechanisms and a novel intervention target for this cluster of conditions. We identified six potential drug repurposing opportunities involving clinically targeted proteins, including LPA and IRF5 for cardiovascular and immune-mediated inflammatory conditions, respectively. Fifteen variants showed discordant effects across phenotypes, suggesting possible adverse consequences of pharmacological intervention; for example, a variant in GIPR reduced risk of obesity and sleep apnoea whilst increasing risk of breast cancer. These findings reveal shared mechanisms underlying MLTC and highlight opportunities for therapeutic development and repurposing, whilst also identifying possible adverse effects.