University of Oulu

Saarentaus, E.C., Havulinna, A.S., Mars, N. et al. Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants. Mol Psychiatry 26, 4884–4895 (2021).

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

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Author: Saarentaus, Elmo Christian1; Havulinna, Aki Samuli1,2; Mars, Nina1;
Organizations: 1Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
2Finnish Institute for Health and Welfare, Helsinki, Finland
3Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, USA
5Department of Genetics, Yale School of Medicine, New Haven, CT, USA
6McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
7Research Unit of Clinical Neuroscience, University of Oulu & Oulu University Hospital, Oulu, Finland
8Northern Finland Birth Cohorts, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
9Stem Cell and Regenerative Biology, Harvard University, Cambridge, USA
10Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
11Department of Public Health, University of Helsinki, Helsinki, Finland
12Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2021-11-25


Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66–0.89]) and lower household income (OR = 0.77 [0.66–0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38–0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32–0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26–0.37]), lower-income (OR = 0.66 [0.57–0.77]), lower subjective health (OR = 0.72 [0.61–0.83]), and increased mortality (Cox’s HR = 1.55 [1.21–1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

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Series: Molecular psychiatry
ISSN: 1359-4184
ISSN-E: 1476-5578
ISSN-L: 1359-4184
Volume: 26
Issue: 9
Pages: 4884 - 4895
DOI: 10.1038/s41380-021-01026-z
Type of Publication: A1 Journal article – refereed
Field of Science: 3112 Neurosciences
Funding: This study was funded by the Sigrid Juselius Foundation, Foundation and the Horizon 2020 Research and Innovation Programme [grant number 667301 (COSYN) to A.P.], the National Institute of Health (Grant no. 1U01MH105666-01), the Swedish Cultural Foundation in Finland (Grant no. 135987), the Finnish Medical Foundation (Grant no. 3264), the Centre of Excellence Complex Disease Genetics (CoECDG, University of Helsinki, Academy of Finland Grant no. 312074 for A.P., Grant no. 312062 for S.R., Grant no. 312073 for J.K. and Grant no. 312075 for M.D.), and the Doctoral School for Population Health (University of Helsinki). S.R. was also supported by the Finnish Foundation for Cardiovascular Research and University of Helsinki HiLIFE Fellow and Grand Challenge grants. NFBC1966 received financial support from the University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. Open Access funding provided by University of Helsinki including Helsinki University Central Hospital.
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