The 22q11.2 deletion syndrome is characterized by great clinical heterogeneity among patients and congenital heart disease is one of the most relevant phenotypes. The etiology of this variability is still poorly understood but complex genetic mechanisms seem to be involved. In addition to variants in the non-deleted 22q11.2 locus, genetic modifiers in other regions of the genome may have an influence on the variability of the phenotypes. One of the main limitations to better explore the contribution of these genetic variants is the small sample size of studies focused on the syndrome, given its rarity. Thus, the present project proposes new approaches that leverage available large-scale data to verify if genetic variants associated with complex traits related to cardiac phenotypes may play a role in the presence of congenital heart disease in patients with 22q11.2 deletion syndrome. For that purpose, we will identify mild intermediate traits associated with the 22q11.2 deletion syndrome through PheWAS and Mendelian Randomization approaches, and then verify if genetic variants associated with these phenotypes may contribute to congenital heart disease in 22q11.2 deletion syndrome cohorts. In addition, CNVs encompassing the 22q11.2 region will be evaluated in the UK Biobank cohort to test for selection bias, with the hypothesis that individuals carrying these CNVs present a lower than expected polygenic risk score for the identified traits. The joint presence of the deletion and genetic risk scores will be assessed with liability threshold models. The results of this study may help to identify potential genetic modifiers to cardiac defects in the 22q11.2 deletion syndrome and improve the understanding of the 22q11.2 region complexity.
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