Identification of five novel genetic loci related to facial morphology by genome-wide association studies

Abstract

Background: Face morphology is strongly determined by genetic factors. However, only a small number of genes related to face morphology have been identified to date. Here, we performed a two-stage genome-wide association study (GWAS) of 85 face morphological traits in 7569 Koreans (5643 in the discovery set and 1926 in the replication set).

Results: In this study, we analyzed 85 facial traits, including facial angles. After discovery GWAS, 128 single nucleotide polymorphisms (SNPs) showing an association of P < 5 × 10^{- 6} were selected to determine the replication of the associations, and meta-analysis of discovery GWAS and the replication analysis resulted in five genome-wide significant loci. The OSR1-WDR35 [rs7567283, G allele, beta (se) = -0.536 (0.096), P = 2.75 × 10^{- 8}] locus was associated with the facial frontal contour; the HOXD1-MTX2 [rs970797, A allele, beta (se) = 0.015 (0.003), P = 3.97 × 10^{- 9}] and WDR27 [rs3736712, C allele, beta (se) = 0.293 (0.048), P = 8.44 × 10^{- 10}] loci were associated with eye shape; and the SOX9 [rs2193054, C allele, beta (se) (ln-transformed) = -0.007 (0.001), P = 6.17 × 10^{- 17}] and DHX35 [rs2206437, A allele, beta (se) = -0.283 (0.047), P = 1.61 × 10^{- 9}] loci were associated with nose shape. WDR35 and SOX9 were related to known craniofacial malformations, i.e., cranioectodermal dysplasia 2 and campomelic dysplasia, respectively. In addition, we found three independent association signals in the SOX9 locus, and six known loci for nose size and shape were replicated in this study population. Interestingly, four SNPs within these five face morphology-related loci showed discrepancies in allele frequencies among ethnic groups.

Conclusions: We identified five novel face morphology loci that were associated with facial frontal contour, nose shape, and eye shape. Our findings provide useful genetic information for the determination of face morphology.

Keywords: DHX35; Face morphology; GWAS; HOXD1-MTX2; Korean; OSR1-WDR35; SOX9; WDR27.

Fig. 1

Facial points used for the facial traits. The participants were photographed in both frontal and profile views, and 23 frontal and seven lateral face points were extracted (modified from Fig. 1 of reference [34]). Facial phenotypes, such as distance, angle, and area, were measured based on in-house facial data acquisition software. a Points in the right eye, b points in the left eye, c points and areas in frontal images, d points in lateral images

Fig. 2

Regional association plots for five novel loci across a 1-Mb window. Association of individual SNPs in the discovery GWAS plotted as −log₁₀(P) against the chromosomal base-pair position. The y-axis on the right shows the recombination rate, estimated from the HapMap CHB and JPT populations. P-values are from the discovery phase. The purple circle and diamond represent the results of discovery and meta-analysis (Phase 1 + 2), respectively. Seven signal plots for five novel SNPs are illustrated, which show the genome-wide significant P-values in the meta-analysis (Phase 1 + 2). a rs7567283 of the right facial angle of en-ex-go [(A) enR-exR-goR], b rs970797 of the tangent line angle of er3 [(A) Tan_er3], c rs970797 of the tangent line angle of el3 [(A) Tan_el3], d rs3736712 of eye tail length (psR-exR), e rs2193054 of profile nasal angle [(A) n-prn-sn], f rs2193054 of nasal tip protrusion [(H) prn-sn], and g rs2206437 of subnasal width (sbalR-sbalL)

Fig. 3

Associated facial traits for five novel SNPs. Five novel SNPs and the associated facial traits are illustrated on the frontal, lateral, and eye images. (1) rs7567283 (OSR1-WDR35) and right facial angle, (2) rs970797 (HOXD1-MTX2) and left and right curvature of the upper eyelid, (3) rs3736712 (WDR27) and eye tail length, (4) rs2193054 (SOX9) and nose shape (angle and height), and (5) rs2206437 (DHX35) and subnasal width

Fig. 4

Association signals in the SOX9 locus and genomic environment surrounding SOX9 across a 4-Mb window. The upper five panels present multiple signals, (1) rs9915190, (2) rs1859979, (3) rs9910003, and (4) rs2193054, in the SOX9 locus for five nose traits: nasal tip protrusion [(H) prn-sn], nasal bridge depth [(H) n-prn], profile nasal area [(AR) n-prn-sn], nasolabial angle [(A) prn-sn], and profile nasal angle [(A) n-prn-sn]. These are plotted as −log₁₀(P) against base-pair position on chromosome 17 (Mb) and all P-values are from the discovery phase. The sixth panel shows genes and regulatory domains. Gray boxes represent approximate boundaries of translocation breakpoint clusters, and black boxes represent microdeletions. (a) Sp4 [31], (b) F1 [31], (c) Pierre Robin sequence (PRS) breakpoint cluster [31, 32], (d) distal breakpoint cluster [30], (e) proximal breakpoint cluster [30], and (f) Sp2 [31]. The last panel presents LD blocks based on the HapMap database (HapMap Phase II JPT + CHB, hg18)