Ioanna Katzourou, Marianne B.M. van den Bree, 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 P. Clayton, Golam Khandaker, Daniel Stow, Nicolas Timpson, Ruby Tsang, Megan L. Wood, Megan Wood, George Kirov, James Walters, Michael J. Owen, Peter Holmans, Marianne B.M. van den Bree, Marianne B.M. van den Bree
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.