Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using SNP-chip data, comprising over 6000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval [0.98%,3.3%]). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasising that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p ¼ 1.47 3 10 À54 ) and is also associated with increased levels of total cholesterol (p ¼ 1.22 3 10 À28 ) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p ¼ 4.81 3 10 À21 ) and alanine (p ¼ 6.14 3 10 À12 ) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p ¼ 6.24 3 10 À10 ), which was also found to be strongly associated with increased glycoprotein level (p ¼ 3.53 3 10 À35 ). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

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