Analyses stratified by maternal age and recombination further characterize genes associated with maternal nondisjunction of chromosome 21

Objective In our previous work, we performed the first genome‐wide association study to find genetic risk factors for maternal nondisjunction of chromosome 21. The objective of the current work was to perform stratified analyses of the same dataset to further elucidate potential mechanisms of genetic risk factors. Methods We focused on loci that were statistically significantly associated with maternal nondisjunction based on this same dataset in our previous study and performed stratified association analyses in seven subgroups defined by age and meiotic recombination profile. In each analysis, we contrasted a different subgroup of mothers with the same set of fathers, the mothers serving as cases (phenotype: meiotic nondisjunction of chromosome 21) and the fathers as controls. Results Our stratified analyses identified several genes whose patterns of association are consistent with generalized effects across groups, as well as other genes that are consistent with specific effects in certain groups. Conclusions While our results are epidemiological in nature and cannot conclusively prove mechanisms, we identified a number of patterns that are consistent with specific mechanisms. In many cases those mechanisms are strongly supported by available literature on the associated genes. Key Points What's already known about this topic? Advanced maternal age and altered meiotic recombination are important risk factors for meiotic nondisjunction of chromosome 21. Our previous research found that nondisjunction of chromosome 21 is associated with common genetic variants in and near genes involved with meiotic processes. Several mechanisms have been proposed to explain how errors in meiosis I (MI) and meiosis II (MII) relate to maternal age and recombination, but the role of genetics is not well‐understood. What does this study add? We further dissect genetic associations with MI and MII errors by performing stratified analyses of mothers of children with Down syndrome, grouping by maternal age and recombination pattern. Our results provide insight into how genetic variation may contribute to specific nondisjunction mechanisms.