Genome-Wide Association Study and Rare Variant Association Studies of Strabismus in the All of Us Research Program

Objective Despite significant evidence of a genetic contribution to strabismus, precise genetic mechanisms have not been identified. There are distinct population differences in the prevalence of strabismus and its subtypes. This study aimed to explore the genetic contributions to strabismus in different ancestral groups. Design Case-control. Participants The All of Us Research Program includes genotypic and phenotypic data from a diverse population of adults (age ≥ 18 years) across the United States. Among participants with whole genome sequences available, strabismus cases were identified based on diagnosis codes. Participants with conditions associated with acquired strabismus, such as trauma, thyroid eye disease, tumor or stroke were excluded from the case/control cohorts. The final cohort consisted of 1579 cases and 121,490 controls of European (EUR) ancestry, 235 cases and 40,602 controls of Admixed American (AMR) ancestry, and 365 cases and 53577 controls of African (AFR) ancestry. Individuals of other ancestral groups were not included due to small numbers of affected participants. Methods Genome-wide association study (GWAS) of common variants (minor allele frequency >1%) and rare variant association study (RVAS) at the gene level for strabismus. Main Outcome Measures Individual single-nucleotide polymorphisms (SNPs) significantly associated with strabismus and genes with significant burden of rare variants in strabismus Results GWAS identified 1 locus with three significant SNPs (rs2247113, rs2667037, and rs2715926) in intron1 of PLA2R1 in the AFR group, and two loci, one in RIMBP2 intron (rs184071225) and one intergenic (rs191788703), in the AMR group. RVAS revealed 33 genes with a statistically significant (p-value < 5x10 -5 ) increased burden of variants: 9 in the EUR cohort: ZNF468, CMYA5, NSUN4, TEX45, ICAM3, ADAMTS20, FANCI, HLA-DQB1, and GRIN3B ; 14 in the AMR cohort: RIMBP1, UCKL1, EHBP1L1, CLTCL1, HELB, TULP2, APOB, SMPD3, OBSCN, NLRP8, PLOD1, NUP214, OR6J1 , and NOP10 ; and 10 in the AFR cohort: C4orf54, PIGG, OR10D3, MKNK1, KNCN, MS4A14, CSN2, BDKRB1, IL1RL1, and ISM2. Conclusions Genetic associations with strabismus differed between ancestry groups, although genes in similar pathways, such as synaptic signaling and structural muscle proteins were found in multiple groups. This highlights the importance of including diverse populations in studies of genetic associations and suggests that multiple pathways may lead to strabismus in different population groups.