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. 2020 Jun 25;21(Suppl 2):132.
doi: 10.1186/s12881-020-01068-0.

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations

Aroon T Chande  1   2   3 , Lavanya Rishishwar  2   3 , Andrew B Conley  2   3 , Augusto Valderrama-Aguirre  1   3   4   5 , Miguel A Medina-Rivas  3   6 , I King Jordan  7   8   9
Affiliations

Ancestry effects on type 2 diabetes genetic risk inference in Hispanic/Latino populations

Aroon T Chande et al. BMC Med Genet. .

Abstract

Background: Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations.

Methods: Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here.

Results: T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences.

Conclusions: T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

Keywords: Antioquia; Chocó; Colombia; Genetic ancestry; Genetic risk; Hispanic/Latino (HL); Polygenic risk score (PRS); Population genetics; Type 2 diabetes (T2D).

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Diabetes global prevalence and population disparities. a Diabetes prevalence distributions shown for (a) the seven world health organization (WHO) geographic regions and (b) the four WHO income groups. (c) Diabetes prevalence for United States (US) census race/ethnicity groups. d Hispanic/Latino (HL) diabetes prevalence in the US broken down by country (region) of origin and shown separately for males (black) and females (white)
Fig. 2
Fig. 2
Genome wide association studies (GWAS) on type 2 diabetes (T2D). The number of (a) GWAS and the number of (b) SNP-associations per GWAS trait are shown, with T2D values in red. c The fractions of continental ancestry groups represented in GWAS cohorts are shown for all GWAS and for T2D GWAS alone
Fig. 3
Fig. 3
T2D genetic risk and observed prevalence in Colombia. a T2D polygenic risk score distributions are shown for Antioquia (green) and Chocó (purple). b T2D polygenic risk scores for individuals from Antioquia and Chocó regressed against their percent African ancestry. c Observed T2D diabetes prevalence for Antioquia (green), Chocó (purple), and Colombia overall (gray). d Observed T2D relative genetic risk Chocó/Antioquia compared to the null distribution of relative genetic risk between the two populations
Fig. 4
Fig. 4
T2D genetic risk comparison in Colombia based on different GWAS cohort continental ancestries. T2D polygenic risk score distributions for Antioquia (green) and Chocó (purple) are shown for SNP associations discovered in patient cohorts with distinct continental ancestries
Fig. 5
Fig. 5
T2D genetic risk and observed prevalence for European-American (EA) and Mexican-American (MA) cohort populations. a T2D polygenic risk score distributions are shown for EA (gold) and MA (green). b T2D polygenic risk scores for EA and MA individuals are regressed against their percent European and percent Native American ancestry. c Observed T2D diabetes prevalence values for EA (gold), MA (green), and the United States overall (gray)
Fig. 6
Fig. 6
T2D genetic risk comparison between European-American (EA) and Mexican-American (MA) cohort populations based on ancestry-specific SNP effects. T2D polygenic risk score distributions for EA (gold) and MA (green) populations are compared for (a) all SNPs with consistent ancestry effects, (b) SNPs with European ancestry-specific effects, (c) SNPs with Mexican ancestry-specific effects, and (d) SNPs with opposing ancestry effects
Fig. 7
Fig. 7
Correcting for ancestry bias in T2D risk inference. The null distribution of T2D relative risk between the EA-MA populations is generated by randomly sampling risk alleles with the same frequency of ancestral/derived alleles as the GWAS source population. The initial observed T2D relative risk is compared to the null distribution to yield a corrected score. The observed T2 relative risk is shown on the distribution (arrow) along with the corrected T2D relative risk value and its significance (upper left)
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