Katzourou, Ioanna K., LINC consortium, Barroso, Inês, Clayton, Julie, Khandaker, Golam, Stow, Daniel, Timpson, Nicolas, Tsang, Ruby, Underwood, Jack  ORCID: https://orcid.org/0000-0003-1731-6039, Wood, Megan, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Walters, James ORCID: https://orcid.org/0000-0002-6980-4053, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412 and van den Bree, Marianne ORCID: https://orcid.org/0000-0002-4426-3254
2026.
Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank.
American Journal of Human Genetics
113
(6)
, pp. 1319-1329.
10.1016/j.ajhg.2026.02.021
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Abstract
Internalizing and cardiometabolic multimorbidity (ICM-MM) represents a major clinical challenge, negatively impacting life expectancy and quality of life and resulting in considerable healthcare costs. Individuals with a copy-number variant associated with increased risk of neurodevelopmental conditions (ND-CNV) are more likely to develop mental or physical ill health; however, the effects on ICM-MM remain poorly understood. We used data from the UK Biobank (ND-CNV N = 7,549, 1.62%) to examine the effect of ND-CNVs on ICM-MM. ICM-MM was defined as a combination of any internalizing condition (depression, anxiety, or somatic symptom disorder) with each of five cardiometabolic conditions (hypertension, dyslipidemia, obesity, type 2 diabetes (T2D), and chronic kidney disease). We also studied whether ICM-MM risk in those with ND-CNVs differed by sex or presence of a deletion versus a duplication. We established associations between dosage-sensitive genes within ND-CNVs and ICM-MM and explored the interaction between the presence of ND-CNVs and polygenic risk scores (PRSs) of internalizing and cardiometabolic traits on ICM-MM risk. The presence of ND-CNVs was associated with ICM-MM (odds ratio [OR] range: 1.21–1.57). Female participants with ND-CNVs were more likely to have any internalizing condition and T2D, and those with a deletion were more likely to have any internalizing condition and obesity. The number of deleted haploinsufficient genes, but not duplicated triplosensitive genes, was associated with ICM-MM. No interactions between ND-CNVs and PRSs were found. We find that ND-CNVs increase the likelihood of ICM-MM, with evidence of sex differences and stronger effects for deletions. Increased clinical awareness can help ameliorate this risk.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine Schools > Psychology |
| Publisher: | Cell Press |
| ISSN: | 0002-9297 |
| Funders: | Medical Research Council |
| Projects: | MR/W014416/1 |
| Date of First Compliant Deposit: | 13 April 2026 |
| Date of Acceptance: | 26 February 2026 |
| Last Modified: | 12 Aug 2026 09:58 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/186336 |
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