Multiancestral GWAS of Dental Malocclusion Identifies Multiple Risk Loci

Malocclusion is a common oral health problem with a strong hereditary component. Previous genetic studies were limited by small sample sizes and low genomic coverage. To address these limitations, we conducted a genome-wide association study (GWAS) using array-based genotype data in 5 large, multiancestral cohorts. The study included 3,405 participants from the United States and its territories, the Philippines, Colombia, and Nigeria. Class II malocclusion was defined as an Angle's class II molar relationship with an overjet >3.5 mm, class III malocclusion as an Angle's class III molar relationship with a negative overjet, and class I malocclusion (controls) as an Angle's class I molar relationship with an overjet of 0 to 3.5 mm. In the vertical plane, an anterior open bite of any magnitude was classified as "open bite," while an overbite >3.5 mm was classified as "deep bite," with controls having an overbite of 0 to 3.5 mm. Multiplanar malocclusion included cases with both sagittal and vertical discrepancies, with controls having an Angle's class I molar relationship, an overjet of 0 to 3.5 mm, and an overbite of 0 to 3.5 mm. GWAS for each phenotype was conducted within individual cohorts before meta-analysis. We identified genome-wide significant associations (P ≤ 5E-08) at 11q22.3 (rs372564249, odds ratio [OR] = 3.12) and 3p24.3 (rs13060317, OR = 2.4) for class II and multiplanar malocclusion, respectively. Additionally, we observed a near-significant signal at 12q15 (rs1261646, OR = 1.9, P = 6.2 × 10^-8) for class II malocclusion and a suggestive association at 1p21.3 (rs7541224, OR = 2.0, P = 1.7 × 10^-7) for class III malocclusion. The 11q22.3 and 3p24.3 loci were QTLs for the PDGFD and SGO1-AS1 genes, and transcriptomic data showed consistent expression of these genes during facial development. These findings provide valuable insights into malocclusion etiology and lay the groundwork for genetic risk score development.