| Title: | Neurodevelopmental copy-number variants increase risk of internalizing and cardiometabolic multimorbidity: Findings from the UK Biobank |
| Journal: | American Journal of Human Genetics |
| Published: | 6 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41946365/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2026.02.021 |
Publication 18088
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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.</p>
43 Authors
- Ioanna K. Katzourou
- LINC consortium
- Marianne B.M. van den Bree
- George Kirov
- Michael J. Owen
- James T.R. Walters
- Peter A. Holmans
- Jane Lynch
- Ioanna K. Katzourou
- Jack F.J. Underwood
- David A. van Heel
- Sarah Finer
- Daniel Stow
- Golam M. Khandaker
- Nicholas J. Timpson
- John A.A. MacLeod
- Julie P. Clayton
- Ruby S.M. Tsang
- Jane Sprackman
- Shahid Khan
- Inês Barroso
- Rupert A. Payne
- Mark Mon-Williams
- Megan L. Wood
- Nabila Ali
- Hilary C. Martin
- Thomas Werge
- Andrés Ingason
- Morteza Vaez
- Lam O. Huang
- Inês Barroso
- Julie Clayton
- Golam Khandaker
- Daniel Stow
- Nicolas Timpson
- Ruby Tsang
- Jack Underwood
- Megan Wood
- George Kirov
- James Walters
- Michael J. Owen
- Peter Holmans
- Marianne B.M. van den Bree
1 Application
| Application ID | Title |
|---|---|
| 79704 | Physical and mental health multimorbidity across the lifespan (LIfespaN multimorbidity research Collaborative: LINC). |
Enabling scientific discoveries that improve human health