Publications by authors named "Timothy A Thornton"

73 Publications

Nicotine metabolism and its association with CYP2A6 genotype among Indigenous people in Alaska who smoke.

Clin Transl Sci 2021 Sep 14. Epub 2021 Sep 14.

Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Prevalence of smoking is higher in Alaska Native and American Indian (ANAI) populations living in Alaska than the general US population. Genetic factors contribute to smoking and cessation rates. The objective of this study was to compare CYP2A6 genetic variation and CYP2A6 enzyme activity toward nicotine in an ANAI population. ANAI (N = 151) people trying to quit smoking were recruited. DNA samples were genotyped for CYP2A6 variants *1X2A, *1B, *2, *4, *9, *10, *12, and *35. Multiple nicotine metabolites were measured in plasma and urine samples, including cotinine and 3'-hydroxycotinine used to determine CYP2A6 activity (e.g., nicotine metabolite ratio [NMR]). We calculated summary statistics for all of the genotypes and metabolites and assigned CYP2A6 activity scores based on known information. We studied the association of CYP2A6 variants with the NMR and smoking histories. The overall frequency of the CYP2A6*1B gain of function allele was high in the ANAI versus non-ANAI populations in other studies. Both *4 null and *9 decrease of function alleles had frequencies similar to previous studies of ANAI populations. In a multivariate analysis, the genotype-inferred CYP2A6 activity score was associated with both plasma and urine NMR (p value = 8.56E-08 and 4.08E-13, respectively). Plasma NMR was also associated with duration of smoking (p value < 0.01) but not urinary total nicotine equivalents uncorrected for creatinine (TNE9 ) or biological sex. Urine NMR was significantly associated (p value < 0.01) with TNE9 . Variation in NMR in this ANAI population is explained in part by CYP2A6 genetic variation.
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http://dx.doi.org/10.1111/cts.13115DOI Listing
September 2021

Genome-wide association study in the Taiwan biobank identifies four novel genes for human height: NABP2, RASA2, RNF41 and SLC39A5.

Hum Mol Genet 2021 Jul 16. Epub 2021 Jul 16.

Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.

Numerous genome-wide association studies (GWASs) have been conducted for the identification of genetic variants involved with human height. The vast majority of these studies, however, have been conducted in populations of European ancestry. Here, we report the first GWAS of adult height in the Taiwan Biobank using a discovery sample of 14 571 individuals and an independent replication sample of 20 506 individuals. From our analysis we generalize to the Taiwanese population genome-wide significant associations with height and 18 previously identified genes in European and non-Taiwanese East Asian populations. We also identify and replicate, at the genome-wide significance level, associated variants for height in four novel genes at two loci that have not previously been reported: RASA2 on chromosome 3 and NABP2, RNF41, and SLC39A5 at 12q13.3 on chromosome 12. RASA2 and RNF41 are strong candidates for having a role in height with copy number and loss of function variants in RASA2 previously found to be associated with short stature disorders, and decreased expression of the RNF41 gene resulting in insulin resistance in skeletal muscle. The results from our analysis of the Taiwan Biobank underscore the potential for the identification of novel genetic discoveries in underrepresented worldwide populations, even for traits, such as height, that have been extensively investigated in large-scale studies of European ancestry populations.
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http://dx.doi.org/10.1093/hmg/ddab202DOI Listing
July 2021

Characterizing the Genetic Architecture of Parkinson's Disease in Latinos.

Ann Neurol 2021 Sep 22;90(3):353-365. Epub 2021 Jul 22.

Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.

Objective: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data.

Methods: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status.

Results: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10 ).

Interpretation: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365.
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http://dx.doi.org/10.1002/ana.26153DOI Listing
September 2021

Admixture mapping reveals the association between Native American ancestry at 3q13.11 and reduced risk of Alzheimer's disease in Caribbean Hispanics.

Alzheimers Res Ther 2021 07 3;13(1):122. Epub 2021 Jul 3.

Institute for Public Health Genetics, University of Washington, Seattle, WA, USA.

Background: Genetic studies have primarily been conducted in European ancestry populations, identifying dozens of loci associated with late-onset Alzheimer's disease (AD). However, much of AD's heritability remains unexplained; as the prevalence of AD varies across populations, the genetic architecture of the disease may also vary by population with the presence of novel variants or loci.

Methods: We conducted genome-wide analyses of AD in a sample of 2565 Caribbean Hispanics to better understand the genetic contribution to AD in this population. Statistical analysis included both admixture mapping and association testing. Evidence for differential gene expression within regions of interest was collected from independent transcriptomic studies comparing AD cases and controls in samples with primarily European ancestry.

Results: Our genome-wide association study of AD identified no loci reaching genome-wide significance. However, a genome-wide admixture mapping analysis that tests for association between a haplotype's ancestral origin and AD status detected a genome-wide significant association with chromosome 3q13.11 (103.7-107.7Mb, P = 8.76E-07), driven by a protective effect conferred by the Native American ancestry (OR = 0.58, 95%CI = 0.47-0.73). Within this region, two variants were significantly associated with AD after accounting for the number of independent tests (rs12494162, P = 2.33E-06; rs1731642, P = 6.36E-05). The significant admixture mapping signal is composed of 15 haplotype blocks spanning 5 protein-coding genes (ALCAM, BBX, CBLB, CCDC54, CD47) and four brain-derived topologically associated domains, and includes markers significantly associated with the expression of ALCAM, BBX, CBLB, and CD47 in the brain. ALCAM and BBX were also significantly differentially expressed in the brain between AD cases and controls with European ancestry.

Conclusion: These results provide multiethnic evidence for a relationship between AD and multiple genes at 3q13.11 and illustrate the utility of leveraging genetic ancestry diversity via admixture mapping for new insights into AD.
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http://dx.doi.org/10.1186/s13195-021-00866-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254995PMC
July 2021

Variant-specific inflation factors for assessing population stratification at the phenotypic variance level.

Nat Commun 2021 06 9;12(1):3506. Epub 2021 Jun 9.

Department of Biostatistics, University of Washington, Seattle, WA, USA.

In modern Whole Genome Sequencing (WGS) epidemiological studies, participant-level data from multiple studies are often pooled and results are obtained from a single analysis. We consider the impact of differential phenotype variances by study, which we term 'variance stratification'. Unaccounted for, variance stratification can lead to both decreased statistical power, and increased false positives rates, depending on how allele frequencies, sample sizes, and phenotypic variances vary across the studies that are pooled. We develop a procedure to compute variant-specific inflation factors, and show how it can be used for diagnosis of genetic association analyses on pooled individual level data from multiple studies. We describe a WGS-appropriate analysis approach, implemented in freely-available software, which allows study-specific variances and thereby improves performance in practice. We illustrate the variance stratification problem, its solutions, and the proposed diagnostic procedure, in simulations and in data from the Trans-Omics for Precision Medicine Whole Genome Sequencing Program (TOPMed), used in association tests for hemoglobin concentrations and BMI.
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http://dx.doi.org/10.1038/s41467-021-23655-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190158PMC
June 2021

Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants.

Arterioscler Thromb Vasc Biol 2021 06 29;41(6):e369-e378. Epub 2021 Apr 29.

Department of Pathology and Laboratory Medicine (N.A.Z., R.P.T., N.C.O.), Larner College of Medicine, University of Vermont, Burlington.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159903PMC
June 2021

In Vivo Functional Effects of a Novel and Common Variant in the Yup'ik Alaska Native Population.

Drug Metab Dispos 2021 May 25;49(5):345-352. Epub 2021 Feb 25.

Departments of Pharmaceutics (L.M.H., K.E.T.), Biostatistics (T.A.T.), and Medicinal Chemistry (A.E.R.), University of Washington, Seattle, Washington; and Department of Obstetrics and Gynecology (S.E.H., B.B.B.), Oregon Health & Science University, Portland, Oregon

Alaska Native people are under-represented in genetic research but have unique gene variation that may critically impact their response to pharmacotherapy. Full resequencing of in a cross-section of this population identified () a novel, relatively common single nucleotide polymorphism hypothesized to confer CYP2C9 poor metabolizer phenotype by disrupting the start codon. is present at a minor allele frequency of 6.3% in Yup'ik Alaska Native people and thus can contribute to the risk of an adverse drug response from narrow-therapeutic-index CYP2C9 substrates such as ()warfarin. This study's objective was to characterize the catalytic efficiency of the Leu1 variant enzyme in vivo by evaluating the pharmacokinetic behavior of naproxen, a probe substrate for CYP2C9 activity, in genotyped Yup'ik participants. We first confirmed the selectivity of ()-naproxen -demethylation by CYP2C9 using activity-phenotyped human liver microsomes and selective cytochrome P450 inhibitors and then developed and validated a novel liquid chromatography mass spectrometry method for simultaneous quantification of ()naproxen, ()-desmethylnaproxen, and naproxen acyl glucuronide in human urine. The average ratio of ()-desmethylnaproxen to unchanged ()naproxen in urine was 18.0 ± 8.0 ( = 11) for the homozygous reference group and 10.3 ± 6.6 ( = 11) for the variant carrier group ( = 0.011). The effect of variation on CYP2C9 function and its potential to alter the pharmacokinetics of drugs metabolized by the enzyme has clinical implications and should be included in a variant screening panel when pharmacogenetic testing in the Alaska Native population is warranted. SIGNIFICANCE STATEMENT: The novel variant in Alaska Native people was recently identified. This study validated ()naproxen as a CYP2C9 probe substrate to characterize the in vivo functional activity of the variant. The results of this pharmacogenetic-pharmacokinetic study suggest that the variant exhibits loss of enzyme activity. This finding may be important to consider when administering narrow-therapeutic-index medications metabolized by CYP2C9 and also compels further investigation to characterize novel genetic variation in understudied populations.
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http://dx.doi.org/10.1124/dmd.120.000301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008381PMC
May 2021

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature 2021 02 10;590(7845):290-299. Epub 2021 Feb 10.

The Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes). In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.
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http://dx.doi.org/10.1038/s41586-021-03205-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875770PMC
February 2021

Embracing Genetic Diversity to Improve Black Health.

N Engl J Med 2021 Mar 10;384(12):1163-1167. Epub 2021 Feb 10.

From the Departments of Clinical Pharmacy (A.O.-O.), Bioengineering and Therapeutic Sciences (A.O.-O.), and Epidemiology and Biostatistics (Y.M.), and the Institute for Human Genetics (A.O.-O.), University of California, San Francisco; and Ancestry LLC (Y.B.) - both in San Francisco; the Departments of Biostatistics and Statistics, University of Washington, Seattle (T.A.T.); and the Department of Radiology, Mayo Clinic, Jacksonville, FL (R.S.).

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http://dx.doi.org/10.1056/NEJMms2031080DOI Listing
March 2021

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

Clin Transl Sci 2021 Jul 27;14(4):1292-1302. Epub 2021 Jan 27.

Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA.

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4β-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.
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http://dx.doi.org/10.1111/cts.12970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301563PMC
July 2021

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine 2021 Jan 6;63:103157. Epub 2021 Jan 6.

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.
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http://dx.doi.org/10.1016/j.ebiom.2020.103157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804602PMC
January 2021

Genome-Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients.

Mov Disord 2021 02 5;36(2):434-441. Epub 2020 Nov 5.

Neuroscience and Cell Death Research Groups, Medical School and Genetic Institute, Universidad Nacional de Colombia, Bogotá, Colombia.

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease.

Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease.

Results: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10 ).

Conclusions: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059262PMC
February 2021

Maternal-fetal genetic interactions, imprinting, and risk of placental abruption.

J Matern Fetal Neonatal Med 2020 09 24:1-10. Epub 2020 Sep 24.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Maternal genetic variations, including variations in mitochondrial biogenesis (MB) and oxidative phosphorylation (OP), are associated with placental abruption (PA). However, the role of maternal-fetal genetic interactions (MFGI) and parent-of-origin (imprinting) effects in PA remain unknown.

Objective: To investigate MFGI in MB-OP, and imprinting effects in relation to risk of PA.

Methods: Among Peruvian mother-infant pairs (503 PA cases and 1052 controls), independent single nucleotide polymorphisms (SNPs), with linkage-disequilibrium coefficient <0.80, were selected to characterize genetic variations in MB-OP (78 SNPs in 24 genes) and imprinted genes (2713 SNPs in 73 genes). For each MB-OP SNP, four multinomial models corresponding to fetal allele effect, maternal allele effect, maternal and fetal allele additive effect, and maternal-fetal allele interaction effect were fit under Hardy-Weinberg equilibrium, random mating, and rare disease assumptions. The Bayesian information criterion (BIC) was used for model selection. For each SNP in imprinted genes, imprinting effect was tested using a likelihood ratio test. Bonferroni corrections were used to determine statistical significance (p-value < 6.4e-4 for MFGI and p-value < 1.8e-5 for imprinting).

Results: Abruption cases were more likely to experience preeclampsia, have shorter gestational age, and deliver infants with lower birthweight compared with controls. Models with MFGI effects provided improved fit than models with only maternal and fetal genotype main effects for SNP rs12530904 (-value = 1.2e-04) in calcium/calmodulin-dependent protein kinase [CaM kinase] II beta (), and, SNP rs73136795 (-value = 1.9e-04) in peroxisome proliferator-activated receptor-gamma (), both MB genes. We identified 320 SNPs in 45 maternally-imprinted genes (including potassium voltage-gated channel subfamily Q member 1 [], neurotrimin [], and, ATPase phospholipid transporting 10 A []) associated with abruption. Top hits included rs2012323 (-value = 1.6E-16) and rs12221520 (-value1.3e-13) in , rs8036892 (-value = 9.3E-17) and rs188497582 in , rs12589854 (-value = 2.9E-11) and rs80203467 (-value = 4.6e-11) in maternally expressed 8, small nucleolar RNA host (), and rs138281088 in solute carrier family 22 member 2 () (-value = 6.8e-9).

Conclusions: We identified novel PA-related maternal-fetal MB gene interactions and imprinting effects that highlight the role of the fetus in PA risk development. Findings can inform mechanistic investigations to understand the pathogenesis of PA.
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http://dx.doi.org/10.1080/14767058.2020.1822314DOI Listing
September 2020

Non-coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women.

Alzheimers Dement 2021 02 23;17(2):215-225. Epub 2020 Sep 23.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Introduction: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis.

Methods: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus.

Results: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease.

Discussion: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.
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http://dx.doi.org/10.1002/alz.12181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920533PMC
February 2021

On the cross-population generalizability of gene expression prediction models.

PLoS Genet 2020 08 14;16(8):e1008927. Epub 2020 Aug 14.

Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.

The genetic control of gene expression is a core component of human physiology. For the past several years, transcriptome-wide association studies have leveraged large datasets of linked genotype and RNA sequencing information to create a powerful gene-based test of association that has been used in dozens of studies. While numerous discoveries have been made, the populations in the training data are overwhelmingly of European descent, and little is known about the generalizability of these models to other populations. Here, we test for cross-population generalizability of gene expression prediction models using a dataset of African American individuals with RNA-Seq data in whole blood. We find that the default models trained in large datasets such as GTEx and DGN fare poorly in African Americans, with a notable reduction in prediction accuracy when compared to European Americans. We replicate these limitations in cross-population generalizability using the five populations in the GEUVADIS dataset. Via realistic simulations of both populations and gene expression, we show that accurate cross-population generalizability of transcriptome prediction only arises when eQTL architecture is substantially shared across populations. In contrast, models with non-identical eQTLs showed patterns similar to real-world data. Therefore, generating RNA-Seq data in diverse populations is a critical step towards multi-ethnic utility of gene expression prediction.
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http://dx.doi.org/10.1371/journal.pgen.1008927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449671PMC
August 2020

Interferon gamma-induced protein 10 (IP-10) and cardiovascular disease in African Americans.

PLoS One 2020 2;15(4):e0231013. Epub 2020 Apr 2.

Department of Genetics, University of North Carolina, Chapel Hill, NC, United States of America.

Biomarkers of chronic inflammation (such as C-reactive protein) have long been associated with cardiovascular disease and mortality; however, biomarkers involved in antiviral cytokine induction and adaptive immune system activation remain largely unexamined. We hypothesized the cytokine interferon gamma inducible protein 10 (IP-10) would be associated with clinical and subclinical cardiovascular disease and all-cause mortality in African Americans. We assessed these associations in the Jackson Heart Study (JHS) cohort and the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. There was a modest association of IP-10 with higher odds of left ventricular hypertrophy (OR = 1.20 (95% confidence interval (CI) 1.03, 1.41) per standard deviation (SD) higher natural log-transformed IP-10 in JHS). We did not observe associations with ankle brachial index, intima-media thickness, or arterial calcification. Each SD higher increment of ln-transformed IP-10 concentration was associated with incident heart failure (hazard ratio (HR) 1.26; 95% CI 1.11, 1.42, p = 4x10-4) in JHS, and with overall mortality in both JHS (HR 1.12 per SD, 95% CI 1.03, 1.21, p = 7.5x10-3) and REGARDS (HR 1.31 per SD, 95% CI 1.10, 1.55, p = 2.0 x 10-3), adjusting for cardiovascular risk factors and C-reactive protein. However, we found no association between IP-10 and stroke or coronary heart disease. These results suggest a role of IP-10 in heart failure and mortality risk independent of C-reactive protein. Further research is needed to investigate how the body's response to chronic viral infection may mediate heart failure and overall mortality risk in African Americans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231013PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117698PMC
July 2020

Coagulation factor VIII: Relationship to cardiovascular disease risk and whole genome sequence and epigenome-wide analysis in African Americans.

J Thromb Haemost 2020 06 20;18(6):1335-1347. Epub 2020 Feb 20.

Department of Epidemiology, University of Washington, Seattle, Washington.

Background: Prospective studies have suggested higher factor VIII (FVIII) levels are an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans.

Objectives: We measured FVIII levels in ~3400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations.

Methods: We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array.

Results: Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant.

Conclusions: Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.
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http://dx.doi.org/10.1111/jth.14741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274883PMC
June 2020

Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations.

PLoS Genet 2019 12 23;15(12):e1008500. Epub 2019 Dec 23.

Genomics Platform, Broad Institute, Cambridge, Massachusetts, United States of America.

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.
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http://dx.doi.org/10.1371/journal.pgen.1008500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953885PMC
December 2019

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics.

Alzheimers Dement 2019 12 9;15(12):1524-1532. Epub 2019 Oct 9.

Department of Biostatistics, University of Washington, Seattle, WA, USA; Department of Statistics, University of Washington, Seattle, WA, USA. Electronic address:

Introduction: Although the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood.

Methods: Logistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome-wide ancestry on AD risk and age at onset.

Results: Among the Caribbean Hispanics, individuals with African-derived ancestry at APOE had 39% lower odds of AD than individuals with European-derived APOE, after adjusting for APOE genotype, age, and genome-wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals.

Discussion: These results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.
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http://dx.doi.org/10.1016/j.jalz.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925639PMC
December 2019

Interrogation of CYP2D6 Structural Variant Alleles Improves the Correlation Between CYP2D6 Genotype and CYP2D6-Mediated Metabolic Activity.

Clin Transl Sci 2020 01 25;13(1):147-156. Epub 2019 Oct 25.

Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, USA.

The cytochrome P450 2D6 (CYP2D6) gene locus is challenging to accurately genotype due to numerous single nucleotide variants and complex structural variation. Our goal was to determine whether the CYP2D6 genotype-phenotype correlation is improved when diplotype assignments incorporate structural variation, identified by the bioinformatics tool Stargazer, with next-generation sequencing data. Using CYP2D6 activity measured with substrates dextromethorphan and metoprolol, activity score explained 40% and 34% of variability in metabolite formation rates, respectively, when diplotype calls incorporated structural variation, increasing from 36% and 31%, respectively, when diplotypes did not incorporate structural variation. We also investigated whether the revised Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations for translating genotype to phenotype improve CYP2D6 activity predictions over the current system. Although the revised recommendations do not improve the correlation between activity score and CYP2D6 activity, perhaps because of low frequency of the CYP2D6*10 allele, the correlation with metabolizer phenotype group was significantly improved for both substrates. We also measured the function of seven rare coding variants: one (A449D) exhibited decreased (44%) and another (R474Q) increased (127%) activity compared with reference CYP2D6.1 protein. Allele-specific analysis found that A449D is part of a novel CYP2D6*4 suballele, CYP2D6*4.028. The novel haplotype containing R474Q was designated CYP2D6*138 by PharmVar; another novel haplotype containing R365H was designated CYP2D6*139. Accuracy of CYP2D6 phenotype prediction is improved when the CYP2D6 gene locus is interrogated using next-generation sequencing coupled with structural variation analysis. Additionally, revised CPIC genotype to phenotype translation recommendations provides an improvement in assigning CYP2D6 activity.
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http://dx.doi.org/10.1111/cts.12695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951848PMC
January 2020

Genetic association testing using the GENESIS R/Bioconductor package.

Bioinformatics 2019 12;35(24):5346-5348

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Summary: The Genomic Data Storage (GDS) format provides efficient storage and retrieval of genotypes measured by microarrays and sequencing. We developed GENESIS to perform various single- and aggregate-variant association tests using genotype data stored in GDS format. GENESIS implements highly flexible mixed models, allowing for different link functions, multiple variance components and phenotypic heteroskedasticity. GENESIS integrates cohesively with other R/Bioconductor packages to build a complete genomic analysis workflow entirely within the R environment.

Availability And Implementation: https://bioconductor.org/packages/GENESIS; vignettes included.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904076PMC
December 2019

GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations.

PLoS One 2019 28;14(6):e0217796. Epub 2019 Jun 28.

Cardiovascular Health Research Unit, University of Washington, Seattle, WA, United States of America.

Background: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.

Methods: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.

Results: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.

Conclusions: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217796PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599128PMC
February 2020

Genetic analyses of diverse populations improves discovery for complex traits.

Nature 2019 06 19;570(7762):514-518. Epub 2019 Jun 19.

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.
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http://dx.doi.org/10.1038/s41586-019-1310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785182PMC
June 2019

Accuracy of Gene Expression Prediction From Genotype Data With PrediXcan Varies Across and Within Continental Populations.

Front Genet 2019 3;10:261. Epub 2019 Apr 3.

Department of Biostatistics, University of Washington, Seattle, WA, United States.

Using genetic data to predict gene expression has garnered significant attention in recent years. PrediXcan has become one of the most widely used gene-based methods for testing associations between predicted gene expression values and a phenotype, which has facilitated novel insights into the relationship between complex traits and the component of gene expression that can be attributed to genetic variation. The gene expression prediction models for PrediXcan were developed using supervised machine learning methods and training data from the Depression Genes and Networks (DGN) study and the Genotype-Tissue Expression (GTEx) project, where the majority of subjects are of European descent. Many genetic studies, however, include samples from multi-ethnic populations, and in this paper we evaluate the accuracy of PrediXcan for predicting gene expression in diverse populations. Using transcriptomic data from the GEUVADIS (Genetic European Variation in Disease) RNA sequencing project and whole genome sequencing data from the 1000 Genomes project, we evaluate and compare the predictive performance of PrediXcan in an African population (Yoruban) and four European ancestry populations for thousands of genes. We evaluate a range of models from the PrediXcan weight databases and use Pearson's correlation coefficient to assess gene expression prediction accuracy with PrediXcan. From our evaluation, we find that the predictive performance of PrediXcan varies substantially among populations from different continents (-test -value < 2.2 × 10), where prediction accuracy is lower in the Yoruban population from West Africa compared to the European-ancestry populations. Moreover, not only do we find differences in predictive performance between populations from different continents, we also find highly significant differences in prediction accuracy among the four European ancestry populations considered (-test -value < 2.2 × 10). Finally, while there is variability in prediction accuracy across different PrediXcan weight databases, we also find consistency in the qualitative performance of PrediXcan for the five populations considered, with the African ancestry population having the lowest accuracy across databases.
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http://dx.doi.org/10.3389/fgene.2019.00261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456650PMC
April 2019

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.

PLoS Genet 2019 04 16;15(4):e1007739. Epub 2019 Apr 16.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, United States of America.

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
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http://dx.doi.org/10.1371/journal.pgen.1007739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467367PMC
April 2019

VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Clin Transl Sci 2019 05 1;12(3):312-320. Epub 2019 Mar 1.

Department of Pharmacy, University of Washington, Seattle, Washington, USA.

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype-phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 -1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.
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http://dx.doi.org/10.1111/cts.12611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510382PMC
May 2019

Genome-wide Significance Thresholds for Admixture Mapping Studies.

Am J Hum Genet 2019 03 14;104(3):454-465. Epub 2019 Feb 14.

Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.

Admixture mapping studies have become more common in recent years, due in part to technological advances and growing international efforts to increase the diversity of genetic studies. However, many open questions remain about appropriate implementation of admixture mapping studies, including how best to control for multiple testing, particularly in the presence of population structure. In this study, we develop a theoretical framework to characterize the correlation of local ancestry and admixture mapping test statistics in admixed populations with contributions from any number of ancestral populations and arbitrary population structure. Based on this framework, we develop an analytical approach for obtaining genome-wide significance thresholds for admixture mapping studies. We validate our approach via analysis of simulated traits with real genotype data for 8,064 unrelated African American and 3,425 Hispanic/Latina women from the Women's Health Initiative SNP Health Association Resource (WHI SHARe). In an application to these WHI SHARe data, our approach yields genome-wide significant p value thresholds of 2.1 × 10 and 4.5 × 10 for admixture mapping studies in the African American and Hispanic/Latina cohorts, respectively. Compared to other commonly used multiple testing correction procedures, our method is fast, easy to implement (using our publicly available R package), and controls the family-wise error rate even in structured populations. Importantly, we note that the appropriate admixture mapping significance threshold depends on the number of ancestral populations, generations since admixture, and population structure of the sample; as a result, significance thresholds are not, in general, transferable across studies.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407497PMC
March 2019

Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.

Hum Mol Genet 2019 02;28(4):675-687

Physiology and Biophysics, University of Mississippi, Jackson, MS, USA.

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
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http://dx.doi.org/10.1093/hmg/ddy387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360325PMC
February 2019

Generalizing polygenic risk scores from Europeans to Hispanics/Latinos.

Genet Epidemiol 2019 02 15;43(1):50-62. Epub 2018 Oct 15.

Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, Massachusetts.

Polygenic risk scores (PRSs) are weighted sums of risk allele counts of single-nucleotide polymorphisms (SNPs) associated with a disease or trait. PRSs are typically constructed based on published results from Genome-Wide Association Studies (GWASs), and the majority of which has been performed in large populations of European ancestry (EA) individuals. Although many genotype-trait associations have generalized across populations, the optimal choice of SNPs and weights for PRSs may differ between populations due to different linkage disequilibrium (LD) and allele frequency patterns. We compare various approaches for PRS construction, using GWAS results from both large EA studies and a smaller study in Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL, n = 12 , 803 ). We consider multiple approaches for selecting SNPs and for computing SNP weights. We study the performance of the resulting PRSs in an independent study of Hispanics/Latinos from the Women's Health Initiative (WHI, n = 3 , 582 ). We support our investigation with simulation studies of potential genetic architectures in a single locus. We observed that selecting variants based on EA GWASs generally performs well, except for blood pressure trait. However, the use of EA GWASs for weight estimation was suboptimal. Using non-EA GWAS results to estimate weights improved results.
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http://dx.doi.org/10.1002/gepi.22166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330129PMC
February 2019
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