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. 2023 Aug 1:14:1181167.
doi: 10.3389/fgene.2023.1181167. eCollection 2023.

Admixture mapping of peripheral artery disease in a Dominican population reveals a putative risk locus on 2q35

Sinead Cullina  1   2 , Genevieve L Wojcik  3 , Ruhollah Shemirani  1 , Derek Klarin  4   5 , Bryan R Gorman  6   7 , Elena P Sorokin  8 , Christopher R Gignoux  9   10   11 , Gillian M Belbin  1   12 , Saiju Pyarajan  6   13 , Samira Asgari  1   2 , Philip S Tsao  4 , Scott M Damrauer  14   15   16 , Noura S Abul-Husn  1   17 , Eimear E Kenny  1   2   17   12
Affiliations

Admixture mapping of peripheral artery disease in a Dominican population reveals a putative risk locus on 2q35

Sinead Cullina et al. Front Genet. .

Abstract

Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have a significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors; however, recent work suggests prevalence may differ between sub-groups. Here, we examined a large cohort of diverse adults in the BioMe biobank in New York City. We observed the prevalence of PAD at 1.7% in EAs vs. 8.5% and 9.4% in AAs and HLs, respectively, and among HL sub-groups, the prevalence was found at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs [OR = 3.15 (95% CI 2.33-4.25), p < 6.44 × 10-14]. To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry and PAD in Dominican BioMe participants (N = 1,813) separately from European, African, and Native American (NAT) continental ancestry tracts. The top association with PAD was an NAT ancestry tract at chromosome 2q35 [OR = 1.96 (SE = 0.16), p < 2.75 × 10-05) with 22.6% vs. 12.9% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA) LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. Efforts to reproduce the signal in other Hispanic cohorts were unsuccessful. In summary, we showed how leveraging health system data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a putative risk locus in a Dominican population.

Keywords: Dominicans; admixture mapping; biobanks; genetic epidemiology; peripheral artery disease.

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Conflict of interest statement

EK received personal fees from Illumina, 23andMe, Allelica, and Regeneron Pharmaceuticals, received research funding from Allelica, and serves as a scientific advisory board member for Encompass Bio, Foresite Labs, and Galateo Bio. NA-H is an employee and equity holder of 23andMe; serves as a scientific advisory board member for Allelica; received personal fees from Genentech, Allelica, and 23andMe; received research funding from Akcea; and was previously employed by Regeneron Pharmaceuticals. ES is an employee of Calico Life Sciences LLC. SA received consulting fees from Variant Bio and Biogen Inc. CG owns stock in 23andMe and serves as an advisory board member for Encompass Bio. DK serve as scientific advisor to Bitterroot Bio, Inc. SMD receives research support from RenalytixAI and Novo Nordisk, outside the scope of the current research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Forest plot comparing odds ratio of peripheral artery disease across diverse genetic ancestry groups in BioMe compared to the non-Jewish European population. Error bars represent 95% confidence intervals. Model 1: PAD ∼ population group + age + sex, model 2: PAD ∼ model 1 + BMI, and model 3: PAD ∼ model 2 + T2D + TG + TC + HDL.
FIGURE 2
FIGURE 2
Admixture mapping results stratified based on EUR (blue), AFR (brown), and NAT (red) haplotypes. Genome-wide significance threshold is indicated by the dashed black line.
FIGURE 3
FIGURE 3
Comparison of ancestry signal Vs. SNP level signal. Native American (NAT) admixture mapping signal is depicted in red showing the PAD association signal compared to the individual SNP associations in gray. The location of genes within this region is depicted in orange in the lower box. Physical positions are build GRCh 37.
FIGURE 4
FIGURE 4
(A) Fine-mapping the 5 Mb region on chromosome 2 (215,000,000–220,000,000) using conditional analysis. Two tag SNPs, rs78529201 and rs77979649, increase the NAT admixture mapping signal toward 0 when included in the association model. (B) Bar plot showing the breakdown of PAD incidence by Native American (NAT) ancestry at admixture mapping peak (2:216,636,519) and rs78529201 carrier status (N = sample size).
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