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

Abstract

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.

The individual and global impact of copy number variants on complex human traits

“…Confirming the deleterious influence of a high CNV load on anthropometric traits (Dauber et al, 2011;Macé et al, 2017;Wheeler et al, 2013) and EA (Kendall et al, 2017;Männik et al, 2015;Saarentaus et al, 2021), we extended this observation to 36 additional traits, including socio-economic factors and global health biomarkers. Hypothesizing a link between telomere length and CNV formation, we tested whether the trait associated with the CNV burden but did not find any association.…”

The individual and global impact of copy-number variants on complex human traits

“…Confirming the deleterious influence of a high CNV load on anthropometric traits 17 , 117 , 118 and EA 11 , 119 , 120 in a non-clinical cohort, we extended this observation to over 30 global health biomarkers. We show how the CNV burden—limited to large and rare CNVs detectable by microarrays—shapes intermediate molecular phenotypes that predate or are consequences of disease processes in a population-based cohort, consistent with its known contribution to a wide range of disorders.…”

Rare copy-number variants as modulators of common disease susceptibility

“…Corroborating the deleterious impact of rare CNVs on an individual's health parameters, socioeconomic status, and lifespan [21,22,26,27,33,[97][98][99][100], we here speculate that the CNV burden acts on the latter by increasing risk for a broad range of common diseases beyond their known role in neuropsychiatric disorders [5][6][7][8]. While both duplications and deletions contributed to increased disease risk, the deletion burden's impact was much stronger-especially for metabolic, psychiatric, pulmonary, and musculoskeletal diseases-in line with the commonly accepted view that deletions tend to be more deleterious.…”