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 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.

Sex differences in short- and long-term case-fatality of myocardial infarction.

Declining trends in case fatality (CF) of MI events have been generally reported in western countries. It is, however, not clear whether the development has been equally beneficial in both sexes. Data from two large population based registers, FINAMI and the Finnish National Cardiovascular Disease Register (CVDR) were used to determine whether the CF of incident MI events has declined less in women than in men. All patients aged 35 and over were included. CF was calculated for different time periods after the onset of the MI event, the main emphasis was in pre-hospital, 28-day, and 1-year CF. Figures were compared between two study periods: 1994-1996 and 2000-2002. A total of 6,342 incident MI events were recorded in FINAMI and 117,632 events in CVDR during the study periods. Comparison between the two study periods showed that the CF was generally declining. However, a slower decline in short-term CF was seen among young (aged<55 years) women (P for sex by study period interaction in pre-hospital CF=0.028 in FINAMI and 0.003 in CVDR, and for 28-day CF P=0.016 in FINAMI and <0.0001 in CVDR). In conclusion, the short and long-term prognosis of MI events has improved in both sexes. Pre-hospital CF has declined less among younger women than among men and among older women. This slower decline in early CF was responsible for the slower improvement in 28-day and 1-year prognosis in young women.