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.
Keywords: Down syndrome; GWAS; aneuploidy; nondisjunction; recombination; stratified analysis; trisomy 21.
© 2021 John Wiley & Sons Ltd.