Krätschmer, I.; Hegemann, L.; Palsson, G.; Hofmeister, R.; Richmond, A.; Hayward, C.; Andreassen, O. A.; Jugessur, A.; Sonderby, I. E.; Askelund, A. D.; Team, E. B. R.; Kutalik, Z.; Marioni, R. E.; Hardarson, M. T.; Stefansson, O. A.; Jonsson, H.; Kharchenko, P.; Stefansson, K.; Halldorsson, B. V.; Havdahl, A.; Robinson, M. R.

Sexual reproduction uses a specialized cell division called meiosis, in which a single round of DNA replication is followed by two cell divisions to create haploid gametes. Genetic recombination in meiosis assures faithful segregation of chromosomes and establishes patterns of genetic linkage and inheritance. Meiotic recombination is thus a fundamental genomic process that shapes major features of the genomic landscape, influences mutation, and creates genetic diversity. The genetic basis of between-individual variation in the occurrence and genomic location of meiotic recombination events remains poorly understood in humans. In particular, we lack an understanding of whether the same DNA regions shape variation in recombination rates across studies. We address this by curating 112,144 maternal and 78,653 paternal meiosis events (parent-child pairs) across cohorts from four countries, creating the largest dataset of its kind. We identify 58 independent genomic regions associated with the occurrence and genomic location of recombination events, 24 of which are unique across phenotypes. Of the 24 unique regions, 6 are novel and specific to female meiotic recombination harboring genes linked to ovarian function, a 7th novel region is linked to male recombination. Many regions have significant sex-dependent effects across studies. We estimate the between-sex genetic correlation for meiotic recombination rate to be 0.374 (0.072 SD), which captures the extent to which the genetic factors influencing a trait in one sex also impact the same trait in the other. 30-40% of the individual-level variation in recombination rate is attributable to DNA markers, of which only 37.7% (2.7% SD) and 47.1% (3.8% SD) is attributable to previously known global modulators of meiotic recombination, in females and males respectively. We create a polygenic predictor that significantly predicts recombination rates of both women and men after adjusting for age and year of birth. We find significant correlations between female meiotic recombination, reproductive outcomes and reproductive aging, after adjusting for study ascertainment. In the largest meta-analysis to date of human meiotic recombination, we identify novel loci with sex-specific effects that influence male and female recombination rate across multiple cohorts.