Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
Finnish Institute for Health and Welfare, Helsinki, Finland.
Mol Psychiatry. 2021 Sep;26(9):4884-4895. doi: 10.1038/s41380-021-01026-z. Epub 2021 Feb 1.
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.
拷贝数变异（CNVs）与综合征和严重神经精神障碍（SNPDs）相关，如智力障碍、癫痫、精神分裂症和双相情感障碍。尽管被认为是高影响力的，但 CNVs 也在普通人群中观察到。这在评估其临床意义时带来了诊断挑战。为了估计 CNV 携带者和非携带者在一般健康和幸福感方面的表型差异，我们比较了与三个全基因组多基因风险评分（PRS）相关的 SNPD 相关 CNVs 对健康、认知和社会经济表型的影响，这三个 PRS 来自两个芬兰队列（FINRISK，n=23053 和 NFBC1966，n=4895）。重点是研究 CNV 携带者和 PRS 极端值，他们没有 SNPD 诊断。我们在 744 名研究参与者（2.66%）中确定了高风险 CNVs（DECIPHER CNVs、风险基因缺失或大于 1 Mb 的 CNVs），其中 36 名（4.8%）患有已诊断的 SNPD。在其余 708 名未受影响的携带者中，我们观察到较低的教育程度（EA；OR=0.77 [95%CI 0.66-0.89]）和较低的家庭收入（OR=0.77 [0.66-0.89]）。与收入相关的 CNVs 也降低了家庭收入（OR=0.50 [0.38-0.66]），具有医疗后果的 CNVs 降低了主观健康（OR=0.48 [0.32-0.72]）。PRS 的影响更为广泛。在 EA 的 PRS 最低极端值中，我们观察到较低的 EA（OR=0.31 [0.26-0.37]）、较低的收入（OR=0.66 [0.57-0.77]）、较低的主观健康（OR=0.72 [0.61-0.83]）和更高的死亡率（Cox 的 HR=1.55 [1.21-1.98]）。用于智力的 PRS 具有类似的影响，而用于精神分裂症的 PRS 则不会影响这些特征。我们得出的结论是，与常见遗传变异极值个体相比，大多数携带高风险 CNV 但无 SNPD 诊断的工作年龄个体对发病率和死亡率有适度影响，对收入和教育程度的影响有限。我们的研究结果强调，传统高风险变异（如 CNVs）的贡献应该在更广泛的遗传背景下进行分析，而不是孤立地进行评估。
