“Polygenic Burden Has Broader Impact on Health, Cognition, and Socioeconomic Outcomes Than Most Rare and High-Risk Copy Number Variants”, Elmo Christian Saarentaus, Aki Samuli Havulinna, Nina Mars, Ari Ahola-Olli, Tuomo Tapio Johannes Kiiskinen, Juulia Partanen, Sanni Ruotsalainen, Mitja Kurki, Lea Martta Urpa, Lei Chen, Markus Perola, Veikko Salomaa, Juha Veijola, Minna Männikkö, Ira M. Hall, Olli Pietiläinen, Jaakko Kaprio, Samuli Ripatti, Mark Daly, Aarno Palotie2021-02-01 (, , , ; similar)⁠:

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 NFBC196658ya, 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.

[Keywords: bipolar disorder, depression, genetics, predictive markers, schizophrenia]

Figure 3: Health impact of high-risk CNVs and PRSs in Finnish cohorts: A: Hazard ratios in a Cox regression model for mortality in unaffected carriers of high-risk CNVs and individuals at the PRS extremes in FINRISK (<em>n</em> = 22,210). ID gene deletions are not pictured as there were no deaths during follow-up for carriers of this type of CNV. B: Incidence rate ratio (IRR) of high-risk CNVs and PRS extremes in a Poisson regression model of the Charlson comorbidity index (CCI) in FINRISK individuals with no SNPD (<em>n</em> = 22,210). The incidence of one CCI unit was more than 3.5 higher in ID gene deletion carriers than in individuals with no high-risk CNV. C, D: Impact of CNVs and PRS outlier status on socioeconomic status and health. The odds of low SES and poor health were highest for individuals with low PRSIQ, and to a lesser extent for individuals at the lowest extreme of PRSEA (A). The odds of high SES and good health was lowest for individuals at the lowest extreme of PRSEA, and to a lesser extent for individuals at the lowest extreme of PRSIQ (B). Effects meta-analyzed using a random-effects assumption are denoted by triangles, otherwise, a fixed-effect assumption was made. The Bonferroni-adjusted p-value is denoted above the point estimate of each variant.
Figure 3: Health impact of high-risk CNVs and PRSs in Finnish cohorts: A: Hazard ratios in a Cox regression model for mortality in unaffected carriers of high-risk CNVs and individuals at the PRS extremes in FINRISK (n = 22,210). ID gene deletions are not pictured as there were no deaths during follow-up for carriers of this type of CNV. B: Incidence rate ratio (IRR) of high-risk CNVs and PRS extremes in a Poisson regression model of the Charlson comorbidity index (CCI) in FINRISK individuals with no SNPD (n = 22,210). The incidence of one CCI unit was more than 3.5 higher in ID gene deletion carriers than in individuals with no high-risk CNV. C, D: Impact of CNVs and PRS outlier status on socioeconomic status and health. The odds of low SES and poor health were highest for individuals with low PRSIQ, and to a lesser extent for individuals at the lowest extreme of PRSEA (A). The odds of high SES and good health was lowest for individuals at the lowest extreme of PRSEA, and to a lesser extent for individuals at the lowest extreme of PRSIQ (B). Effects meta-analyzed using a random-effects assumption are denoted by triangles, otherwise, a fixed-effect assumption was made. The Bonferroni-adjusted p-value is denoted above the point estimate of each variant.