Lung development genes, adult lung function and cognitive traits

Mohammad Talaei; Sheena Waters; Laura Portas; Benjamin M Jacobs; James W Dodd; Charles R Marshall; Cosetta Minelli; Seif O Shaheen

doi:10.1093/braincomms/fcae380

Lung development genes, adult lung function and cognitive traits

Brain Commun. 2024 Nov 1;6(6):fcae380. doi: 10.1093/braincomms/fcae380. eCollection 2024.

Authors

Mohammad Talaei¹, Sheena Waters¹, Laura Portas^{2

3}, Benjamin M Jacobs¹, James W Dodd^{4

5}, Charles R Marshall¹, Cosetta Minelli⁶, Seif O Shaheen^{1

7}

Affiliations

¹ Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London EC1M 6BQ, UK.
² Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
³ Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7LF, UK.
⁴ MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol BS8 2BN, UK.
⁵ Academic Respiratory Unit, Southmead Hospital, University of Bristol, Bristol BS10 5NB, UK.
⁶ National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
⁷ Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.

Abstract

Lower lung function is associated with lower cognitive function and an increased risk of dementia. This has not been adequately explained and may partly reflect shared developmental pathways. In UK Biobank participants of European ancestry, we tested the association between lung function measures (forced vital capacity and forced expiratory volume in 1 s to forced vital capacity ratio; n = 306 476) and cognitive traits including nine cognitive function test scores (n = 32 321-428 609), all-cause dementia, Alzheimer's disease and vascular dementia (6805, 2859 and 1544 cases, respectively, and ∼421 241 controls). In the same population, we derived summary statistics for associations between common genetic variants in 55 lung development genes and lung function measures and cognitive traits using adjusted linear/logistic regression models. Using a hypothesis-driven Bayesian co-localization analysis, we finally investigated the presence of shared genetic signals between lung function measures and cognitive traits at each of these 55 genes. Higher lung function measures were generally associated with higher scores of cognitive function tests as well as lower risk of dementia. The strongest association was between forced vital capacity and vascular dementia (adjusted hazard ratio 0.74 per standard deviation increase, 95% confidence interval 0.67-0.83). Of the 55 genes of interest, we found shared variants in four genes, namely: CSNK2B rs9267531 (forced vital capacity and forced expiratory volume in 1 s to forced vital capacity ratio with fluid intelligence and pairs matching), NFATC3 rs548092276 & rs11275011 (forced expiratory volume in 1 s to forced vital capacity ratio with fluid intelligence), PTCH1 rs2297086 & rs539078574 (forced expiratory volume in 1 s to forced vital capacity ratio with reaction time) and KAT8 rs138259061 (forced vital capacity with pairs matching). However, the direction of effects was not in keeping with our hypothesis, i.e. variants associated with lower lung function were associated with better cognitive function or vice versa. We also found distinct variants associated with lung function and cognitive function in KAT8 (forced vital capacity and Alzheimer's disease) and PTCH1 (forced vital capacity and forced expiratory volume in 1 s to forced vital capacity ratio with fluid intelligence and reaction time). The links between CSNK2B and NFATC3 and cognitive traits have not been previously reported by genome-wide association studies. Despite shared genes and variants, our findings do not support the hypothesis that shared developmental signalling pathways explain the association of lower adult lung function with poorer cognitive function.

Keywords: cognitive function; dementia; genes; lung function; shared development.