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1. Human-SARS-CoV-2 interactome and human genetic diversity: TMPRSS2-rs2070788, associated with severe influenza, and its population genetics caveats in Native Americans

Author

Fernanda S.G. Kehdy, Murilo Pita-Oliveira, Mariana M. Scudeler, Sabrina Torres-Loureiro, Camila Zolini, Rennan Moreira, Lucas A. Michelin, Isabela Alvim, Carolina Silva-Carvalho, Vinicius C. Furlan, Marla M. Aquino, Meddly L. Santolalla, Victor Borda, Giordano B. Soares-Souza, Luis Jaramillo-Valverde, Andres Vasquez-Dominguez, Cesar Sanchez Neira, Renato S. Aguiar, Ricardo A. Verdugo, Timothy D. O`Connor, Heinner Guio, Eduardo Tarazona-Santos, Thiago P. Leal, and Fernanda Rodrigues-Soares

Subjects
TMPRSS2, ACE2, Native Americans, SARS-CoV-2, population genomics, Genetics, QH426-470
Abstract

Abstract For human/SARS-CoV-2 interactome genes ACE2, TMPRSS2 and BSG, there is a convincing evidence of association in Asians with influenza-induced SARS for TMPRSS2-rs2070788, tag-SNP of the eQTL rs383510. This case illustrates the importance of population genetics and of sequencing data in the design of genetic association studies in different human populations: the high linkage disequilibrium (LD) between rs2070788 and rs383510 is Asian-specific. Leveraging on a combination of genotyping and sequencing data for Native Americans (neglected in genetic studies), we show that while their frequencies of the Asian tag-SNP rs2070788 is, surprisingly, the highest worldwide, it is not in LD with the eQTL rs383510, that therefore, should be directly genotyped in genetic association studies of SARS in populations with Native American ancestry.

Published
2021
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2. Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes

Author

Meddly L. Santolalla, Fernanda S G Kehdy, Thiago P. Leal, Michel S Naslavsky, Meredith Yeager, Moara Machado, Eduardo Tarazona-Santos, Shane A. Norris, Hanaisa P Sant'Anna, Francisco Pereira Lobo, Victor Borda, Lucas Michelin, Alexandre C. Pereira, Sam M. Mbulaiteye, Robert H. Gilman, Guilherme L. Yamamoto, Edward D. Yeboah, Marcelo R. Luizon, Matthew E. B. Hansen, Sérgio Viana Peixoto, Camila Zolini, Nathalia M. Araujo, Julie Dutil, Timothy D O Connor, Isabela Alvim, Mateus H. Gouveia, Maria Rita Passos-Bueno, Ricardo Lyra, Marilia O. Scliar, Michèle Ramsay, Gilderlanio S. Araújo, Yeda Aparecida de Oliveira Duarte, Heinner Guio, Mayana Zatz, Maria Fernanda Lima-Costa, Wagner C. S. Magalhães, Sarah A. Tishkoff, Ananyo Choudhury, Bernardo L. Horta, Maíra R. Rodrigues, James E. Mensah, Mauricio Lima Barreto, and Ann W. Hsing

Subjects
Male, purl.org/pe-repo/ocde/ford#3.03.04 [https], Endocrinology, Diabetes and Metabolism, Population, Medicine (miscellaneous), Genetic admixture, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Regulatory Sequences, Nucleic Acid, Biology, Polymorphism, Single Nucleotide, Article, Body Mass Index, Young Adult, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, Genetics, Humans, 030212 general & internal medicine, Allele, Young adult, Child, education, Alleles, Aged, Aged, 80 and over, education.field_of_study, Nutrition and Dietetics, purl.org/pe-repo/ocde/ford#3.02.18 [https], Chromosome Mapping, Middle Aged, Genetic architecture, Genetics, Population, Phenotype, Risk factors, Child, Preschool, Cohort, Female, Body mass index, Brazil, Demography
Abstract

Background/objectives: Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil. Subjects/methods: Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European, and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of body mass index (BMI) in three Brazilian population-based cohorts from Northeast (Salvador), Southeast (Bambui), and South (Pelotas). Results: We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p = 2.76e-06). This variant is rare in Europeans but with frequencies of similar to 3% in West Africa and has a strong female-specific effect (95% CI: 2.32-5.65 kg/m(2) per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from Sao Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains similar to 9% among women with morbid obesity from Pelotas, Sao Paulo, and Bambui. The effect size of rs114066381 is at least five times higher than the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects. Conclusions: We identified six candidate SNPs associated with BMI. rs114066381 stands out for its high effect that was replicated and its high frequency in women with morbid obesity. We demonstrate how admixed populations are a source of new relevant phenotype-associated genetic variants.

Published
2021

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