An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population

Abstract

Meniere disease is a complex inner ear disorder with significant familial aggregation. A differential prevalence of familial MD (FMD) has been reported, being 9-10% in Europeans compared to 6% in East Asians. A broad genetic heterogeneity in FMD has been described, OTOG being the most common mutated gene, with a compound heterozygous recessive inheritance. We hypothesize that an OTOG-related founder effect may explain the higher prevalence of FMD in the European population. Therefore, the present study aimed to compare the allele frequency (AF) and distribution of OTOG rare variants across different populations. For this purpose, the coding regions with high constraint (low density of rare variants) were retrieved in the OTOG coding sequence in Non-Finnish European (NFE).. Missense variants (AF < 0.01) were selected from a 100 FMD patient cohort, and their population AF was annotated using gnomAD v2.1. A linkage analysis was performed, and odds ratios were calculated to compare AF between NFE and other populations. Thirteen rare missense variants were observed in 13 FMD patients, with 2 variants (rs61978648 and rs61736002) shared by 5 individuals and another variant (rs117315845) shared by two individuals. The results confirm the observed enrichment of OTOG rare missense variants in FMD. Furthermore, eight variants were enriched in the NFE population, and six of them were in constrained regions. Structural modeling predicts five missense variants that could alter the otogelin stability. We conclude that several variants reported in FMD are in constraint regions, and they may have a founder effect and explain the burden of FMD in the European population.

Keywords: OTOG gene; Exome sequencing; Hearing loss; Meniere’s disease; Population genetics.

Fig. 1

A Representation of the otogelin protein sequence showing the rare variants (AF < 0.01) found in the FMD cohort. It is highlighted in which population (NFE, AFR, EAS, SAS, and AMR) they are most frequent. The circle, triangle, square, diamond, and inverted triangle indicate the presence of the variant in the NFE, AFR, EAS, SAS, and AMR populations, respectively. The colored symbol means that that variant is more frequent in that population. B Otogelin 3D model outlining the positions of the residues where variants were found. In addition, the different domains that constitute the protein are shown in color. The domains have been colored using the Uniprot domain annotations (Q6ZRI0). CTCK: C-terminal cystine knot-like domain (orange). EGF-like: epidermal growth factor-like domain (green). TIL: trypsin inhibitor-like cysteine-rich domain (blue). VWFD: von Willebrand factor C-like domain (purple). The NP_001264198.1 sequence has been used as a reference to annotate protein positions

Fig. 2

Bar plot showing the number of rare missense variants found in OTOG and control genes for each reference population. A NFE, B AFR, C SAS, D EAS, E AMR, and F percentile of the number of rare missense variants in the OTOG gene in the NFE, AFR, EAS, SAS, and AMR reference populations compared to the number of rare missense variants in control genes (AF < 0.01)

Fig. 3

A Heatmap showing the pairwise linkage disequilibrium of variants in the OTOG gene (MAF > 0.05 plus OTOG variants in the FMD cohort) across all populations. Variants with triangular label are the variants found in the FMD cohort. B Heatmap representing the pairwise linkage disequilibrium of FMD variants in the OTOG gene. The two variants not shown in the plots are not annotated in Phase 3 (Version 5) of the 1000 Genomes Project

Fig. 4

Variant density profile along the OTOG CDS in the NFE, AFR, SAS, EAS, and AMR populations calculated with a 201 bp sliding window. High-density regions (HDR; gray areas) and low-density regions (LDR) are those with a high or low number of variants affecting the value of missense variants expected in each population analyzed according to gnomAD v2.1. The eight variants found in the FMD cohort in low-density regions in the NFE population are indicated with triangles. The triangles’ colors (brown, blue, and green) indicate more frequent variants in NFE, AMR, and AFR, respectively. The Red dashed line indicates the threshold density used for each population according to the number of variants expected in the CDS. Variants in the FMD cohort are represented with vertical lines in each plot. Black lines represent frequent variants in the NFE population, green lines in AFR, pink lines in EAS/SAS, and orange in AMR. The NP_001264198.1 sequence has been used as a reference to annotate protein positions