Genome-wide analysis identifies an african-specific variant in SEMA4D associated with body mass index

Abstract

Objective: The prevalence of obesity varies between ethnic groups. No genome-wide association study (GWAS) for body mass index (BMI) has been conducted in continental Africans.

Methods: We performed a GWAS for BMI in 1,570 West Africans (WA). Replication was conducted in independent samples of WA (n = 1,411) and African Americans (AA) (n = 9,020).

Results: We identified a novel genome-wide significant African-specific locus for BMI (SEMA4D, rs80068415; minor allele frequency = 0.008, P = 2.10 × 10^-8 ). This finding was replicated in independent samples of WA (P = 0.013) and AA (P = 0.017). Individuals with obesity had higher serum SEMA4D levels compared to those without obesity (P < 0.0001), and elevated levels of serum SEMA4D were associated with increased obesity risk (OR = 4.2, P < 1 × 10^-4 ). The prevalence of obesity was higher in individuals with the CT versus TT genotypes (55.6% vs. 22.9%).

Conclusions: A novel variant in SEMA4D was significantly associated with BMI. Carriers of the C allele were 4.6 BMI units heavier than carriers of the T allele (P = 0.0007). This variant is monomorphic in Europeans and Asians, highlighting the importance of studying diverse populations. While there is evidence for the involvement of SEMA4D in inflammatory processes, this study is the first to implicate SEMA4D in obesity pathophysiology.

Figure 1

Genome-wide association results. The –log10(p-value) of associations are presented on the y-axis. The x-axis represents loci positions (bp). The dashed lines represent –log10 (2.5×10-8), and -log10(2.5×10-7), for genome-wide and suggestive statistical significance levels, respectively.

Figure 2

SEMA4D regional plot. The x-axis represents positions (Mb), and the y-axis represents –log10(p-values). Recombination rate and r2 scores were calculated from AFR samples in the 1000 Genomes Project (phase1, V3).

Figure 3. Relationships between sSema4D levels, obesity, and rs80068415

(A)Mean and standard deviation of serum Sema4D levels (ng/ml) in obese and non-obese, by gender, with p-values < 0.0001 in males, females, and combined. (B) Mean and standard deviation of BMI (kg/m2) by alleles of rs80068415 (p-value = 0.0007)