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Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants
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 diag...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589645/ https://www.ncbi.nlm.nih.gov/pubmed/33526825 http://dx.doi.org/10.1038/s41380-021-01026-z |
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author | Saarentaus, Elmo Christian Havulinna, Aki Samuli Mars, Nina Ahola-Olli, Ari Kiiskinen, Tuomo Tapio Johannes Partanen, Juulia Ruotsalainen, Sanni Kurki, Mitja Urpa, Lea Martta Chen, Lei Perola, Markus Salomaa, Veikko Veijola, Juha Männikkö, Minna Hall, Ira M. Pietiläinen, Olli Kaprio, Jaakko Ripatti, Samuli Daly, Mark Palotie, Aarno |
author_facet | Saarentaus, Elmo Christian Havulinna, Aki Samuli Mars, Nina Ahola-Olli, Ari Kiiskinen, Tuomo Tapio Johannes Partanen, Juulia Ruotsalainen, Sanni Kurki, Mitja Urpa, Lea Martta Chen, Lei Perola, Markus Salomaa, Veikko Veijola, Juha Männikkö, Minna Hall, Ira M. Pietiläinen, Olli Kaprio, Jaakko Ripatti, Samuli Daly, Mark Palotie, Aarno |
author_sort | Saarentaus, Elmo Christian |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8589645 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85896452021-11-23 Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants Saarentaus, Elmo Christian Havulinna, Aki Samuli Mars, Nina Ahola-Olli, Ari Kiiskinen, Tuomo Tapio Johannes Partanen, Juulia Ruotsalainen, Sanni Kurki, Mitja Urpa, Lea Martta Chen, Lei Perola, Markus Salomaa, Veikko Veijola, Juha Männikkö, Minna Hall, Ira M. Pietiläinen, Olli Kaprio, Jaakko Ripatti, Samuli Daly, Mark Palotie, Aarno Mol Psychiatry Article 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. Nature Publishing Group UK 2021-02-01 2021 /pmc/articles/PMC8589645/ /pubmed/33526825 http://dx.doi.org/10.1038/s41380-021-01026-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Saarentaus, Elmo Christian Havulinna, Aki Samuli Mars, Nina Ahola-Olli, Ari Kiiskinen, Tuomo Tapio Johannes Partanen, Juulia Ruotsalainen, Sanni Kurki, Mitja Urpa, Lea Martta Chen, Lei Perola, Markus Salomaa, Veikko Veijola, Juha Männikkö, Minna Hall, Ira M. Pietiläinen, Olli Kaprio, Jaakko Ripatti, Samuli Daly, Mark Palotie, Aarno Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title | Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title_full | Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title_fullStr | Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title_full_unstemmed | Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title_short | Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
title_sort | polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589645/ https://www.ncbi.nlm.nih.gov/pubmed/33526825 http://dx.doi.org/10.1038/s41380-021-01026-z |
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