Differences In Linkage Disequilibrium Patterns Research Articles

Multivariate adaptive shrinkage improves cross-population transcriptome prediction and association studies in underrepresented populations

Transcriptome prediction models built with data from European-descent individuals are less accurate when applied to different populations because of differences in linkage disequilibrium patterns and allele frequencies. We hypothesized that methods that leverage shared regulatory effects across different conditions, in this case, across different populations, may improve cross-population transcriptome prediction. To test this hypothesis, we made transcriptome prediction models for use in transcriptome-wide association studies (TWASs) using different methods (elastic net, joint-tissue imputation [JTI], matrix expression quantitative trait loci [Matrix eQTL], multivariate adaptive shrinkage in R [MASHR], and transcriptome-integrated genetic association resource [TIGAR]) and tested their out-of-sample transcriptome prediction accuracy in population-matched and cross-population scenarios. Additionally, to evaluate model applicability in TWASs, we integrated publicly available multiethnic genome-wide association study (GWAS) summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study and Pan-ancestry genetic analysis of the UK Biobank (PanUKBB) with our developed transcriptome prediction models. In regard to transcriptome prediction accuracy, MASHR models performed better or the same as other methods in both population-matched and cross-population transcriptome predictions. Furthermore, in multiethnic TWASs, MASHR models yielded more discoveries that replicate in both PAGE and PanUKBB across all methods analyzed, including loci previously mapped in GWASs and loci previously not found in GWASs. Overall, our study demonstrates the importance of using methods that benefit from different populations' effect size estimates in order to improve TWASs for multiethnic or underrepresented populations.

Sequencing-based fine-mapping and in silico functional characterization of the 10q24.32 arsenic metabolism efficiency locus across multiple arsenic-exposed populations.

Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits-The Hispanic/Latino Anthropometry Consortium.

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits

Clinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations (r = 0.81) than with Africans (r = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European (r = 0.94) than with African (r = 0.85) or Japanese (r = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine.

Disease burden and treatment considerations in Krabbe disease: The caregiver perspective

The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.

APOE region molecular signatures of Alzheimer's disease across races/ethnicities

The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E (APOE) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the APOE region emphasizing beneficial and adverse effects of the APOE ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the APOE region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.

Genomic selection prediction models comparing sequence capture and SNP array genotyping methods

The successful application of genomic selection (GS) approaches is dependent on genetic makers derived from high-throughput and low-cost genotyping methods. Recent GS studies in trees have predominantly relied on SNP arrays as the source of genotyping, though this technology has a high entry cost. The recent development of alternative genotyping platforms, tailored to specific species and with low entry cost, has become possible due to advances in next-generation sequencing and genome complexity reduction methods such as sequence capture. However, the performance of these new platforms in GS models has not yet been evaluated, or compared to models developed from SNP arrays. Here, we evaluate the impact of these genotyping technologies on the development of GS prediction models for a Eucalyptus breeding population composed of 739 trees phenotyped for 13 wood quality and growth traits. Genotyping data obtained with both methods were compared for linkage disequilibrium, minor allele frequency, and missing data. Phenotypic prediction methods RR-BLUP and BayesB were employed, while predictive ability using cross validation was used to evaluate the performance of GS models derived from the different genotyping platforms. Differences in linkage disequilibrium patterns, minor allele frequency, missing data, and marker distribution were detected between sequence capture and SNP arrays. However, RR-BLUP and BayesB GS models resulted in similar predictive abilities. These results demonstrate that both genotyping methods are equivalent for genomic prediction of the traits evaluated. Sequence capture offers an alternative for species where SNP arrays are not available, or for when the initial development cost is too high.

Gene variants in AKT1, GCKR and SOCS3 are differentially associated with metabolic traits in Mexican Amerindians and Mestizos

Amerindian ancestry appears to be a risk factor for metabolic diseases (MetD), making Mexicans an ideal population to better understand the genetic architecture of metabolic health. In this study, we determine the association of genetic variants previously reported with metabolic entities, in two Mexican populations, including the largest sample of Amerindians reported to date.We investigated the association of eigth single-nucleotide polymorphisms (SNPs) in AKT1, GCKR, and SOCS3 genes with different metabolic traits in 1923 Mexican Amerindians (MAs) belonging to 57 ethnic groups, and 855 Mestizos (MEZs). The allele frequency of 7/8 SNPs showed significant differences between MAs and MEZs. Interestingly, some alleles were monomorphic in particular ethnic groups, and highly frequent in other ones. With the exception of GCKR rs1260326T, as expected, all SNP frequencies in the MEZ population had intermediate values between its two main ancestral populations (MAs and Iberian populations in Spain [IBS]). We detected ethnic differences in linkage disequilibrium patterns and haplotype structure between MAs and MEZs, possibly due to the high genetic heterogeneity in these populations. Remarkably, AKT1 was associated with hypertension in MEZs, but not in MAs. GCKR was associated with protection against type 2 diabetes (T2D) in MAs, and with hypertriglyceridemia and protection against low HDL Cholesterol (HDL-C) levels in MEZs. The CAT haplotype in SOCS3 was associated with metabolic syndrome (MetS) in MEZs, and correlated with protection against high blood pressure (HBP) and risk for high waist circumference and T2D in MAs. Our results show differential genetic associations with metabolic traits between MAs and MEZs, possibly due to the differences in genetic structure between these Mexican populations.

The Genetic Basis of Type 2 Diabetes in Hispanics and Latin Americans: Challenges and Opportunities.

Type 2 diabetes (T2D) affects 415 million people worldwide, and has a much higher prevalence in Hispanics (16.9%), compared to non-Hispanic whites (10.2%). Genome-wide association studies and whole-genome and whole-exome sequencing studies have discovered more than 100 genetic regions associated with modified risk for T2D. However, the identified genetic factors explain a very small fraction of the estimated heritability. Until recently, little attention has been put in studying other non European populations that suffer from a higher burden of T2D, such as Hispanics/Latinos. In the past few years, genetic studies in Hispanic populations have started to provide new insights into the genetic architecture of T2D in this ancestry group. Of note, several genetic variants that are absent or very rare in non-Hispanic populations but more common in Hispanics have shown from moderate to strong association with T2D and have provided new insights into the biology of T2D, which may be ultimately useful for developing novel therapeutic strategies applicable to all populations. Studying diverse populations can also improve the ability to find the causal variants in known T2D loci by a multi-ancestry fine-mapping approach, which leverages the different patterns of linkage disequilibrium between the causal and the ascertained genetic variants. In this mini-review, we summarize the main genetic findings discovered in Hispanics and discuss the limitations and challenges of performing genetic studies in these populations. Finally, we present possible next steps to make studies in Latino populations more valuable in providing a deeper understanding of T2D and anticipate their future application to the development of predictive and preventive medicine and personalized therapies.

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry.

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.

A survey of sub-Saharan gene flow into the Mediterranean at risk loci for coronary artery disease.

This study tries to find detectable signals of gene flow of Sub-Saharan origin into the Mediterranean in four genomic regions previously associated with coronary artery disease. A total of 366 single-nucleotide polymorphisms were genotyped in 772 individuals from 10 Mediterranean countries. Population structure analyses were performed, in which a noticeable Sub-Saharan component was found in the studied samples. The overall percentage of this Sub-Saharan component presents differences between the two Mediterranean coasts. D-statistics suggest possible Sub-Saharan introgression into one of the studied genomic regions (10q11). We also found differences in linkage disequilibrium patterns between the two Mediterranean coasts, possibly attributable to differential Sub-Saharan admixture. Our results confirm the potentially important role of human demographic history when performing epidemiological studies.

Polygenic risk scores for cigarettes smoked per day do not generalize to a Native American population

BackgroundRecent studies have demonstrated the utility of polygenic risk scores (PRSs) for exploring the genetic etiology of psychiatric phenotypes and the genetic correlations between them. To date, these studies have been conducted almost exclusively using participants of European ancestry, and thus, there is a need for similar studies conducted in other ancestral populations. However, given that the predictive ability of PRSs are sensitive to differences in linkage disequilibrium (LD) patterns and minor allele frequencies across discovery and target samples, the applicability of PRSs developed in European ancestry samples to other ancestral populations has yet to be determined. Therefore, the current study derived PRSs for cigarettes per day (CPD) from predominantly European-ancestry samples and examined their ability to predict nicotine dependence (ND) in a Native American (NA) population sample. Method: Results from the Tobacco and Genetics Consortium’s meta-analysis of genome-wide association studies of CPD were used to compute PRSs in a NA community sample (N=288). These scores were then used to predict ND diagnostic status. Results: The PRS was not significantly associated with liability for ND in the full sample. However, a significant interaction between PRS and percent NA ancestry was observed. Risk scores were positively associated with liability for ND at higher levels of European ancestry, but no association was observed at higher levels of NA ancestry. Conclusion: These findings illustrate how differences in patterns of LD across discovery and target samples can reduce the predictive ability of PRSs for complex traits.

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Considering malaria as a local and focal disease, epidemiological understanding of different ecotypes of malaria can help in devising novel control measures. One of the major hurdles in malaria control lies on the evolution and dispersal of the drug-resistant malaria parasite, Plasmodium falciparum. We herewith present data on genetic variation at the Single Nucleotide Polymorphism (SNP) level in four different genes of P. falciparum (Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps) that confer resistance to different antimalarials in two different eco-epidemiological settings, i.e. Hilly-Forest (HF) and Riverine-Plain (RP), in a high malaria endemic district of Odisha state, India. Greater frequency of antimalarial resistance conferring SNPs and haplotypes was observed in all four genes in P. falciparum, and Pfdhps was the most variable gene among the four. No significant genetic differentiation could be observed in isolates from HF and RP ecotypes. Twelve novel, hitherto unreported nucleotide mutations could be observed in the Pfmdr1 and Pfdhps genes. While the Pfdhps gene presented highest haplotype diversity, the Pfcrt gene displayed the highest nucleotide diversity. When the data on all the four genes were complied, the isolates from HF ecotype were found to harbour higher average nucleotide diversity than those coming from RP ecotype. High and positive Tajima's D values were obtained for the Pfcrt and Pfdhfr genes in isolates from both the HF and RP ecotypes, with statistically significant deviation from neutrality in the RP ecotype. Different patterns of Linkage Disequilibrium (LD) among SNPs located in different drug-resistant genes were found in the isolates collected from HF and RP ecotypes. Whereas in the HF ecotype, SNPs in the Pfmdr1 and Pfdhfr were significantly associated, in the RP ecotype, SNPs located in Pfcrt were associated with Pfmdr1, Pfdhfr and Pfdhps. These findings provide a baseline understanding on how different micro eco-epidemiological settings influence evolution and spread of different drug resistance alleles. Our findings further suggest that drug resistance to chloroquine and sulfadoxine–pyrimethamine is approaching fixation level, which requires urgent attention of malaria control programme in India.

Genetic Susceptibility Loci for Childhood Acute Lymphoblastic Leukemia Among Japanese

Scrutiny of the human genome through evaluation of common genetic variants has revealed hundreds of disease susceptibility loci. In childhood acute lymphoblastic leukemia (ALL), six regions that have replicated in several populations are now considered known susceptibility loci (ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, and GATA3), but their effects have yet to be fully confirmed in populations of non-European ancestry. Targeted validation attempts based on the same SNPs originally identified in European ancestral populations have been performed in East Asians, but findings have been inconsistent. This may be due to differences in linkage disequilibrium patterns, allele frequency, and/or magnitude of effect between Europeans and East Asians; thus a comprehensive characterization of genetic variation across the targeted genetic loci is required for an appropriate validation attempt in different populations.Using a large network of hospitals within the Tokyo Children's Cancer Study Group, saliva samples from previously diagnosed childhood ALL patients (aged 0-19 years) were collected between December 2012 and May 2015. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed and resulted in the inclusion of a total of 570 ALL patients, with genetic data available for up to about 500,000 SNPs after quality control exclusions. Control genome-wide data were available for 2,712 previously genotyped samples from the Nagahama Study Group and Aichi Cancer Center Study, Japan. SNP imputation was performed on the combined case-control dataset using ShapeIT and Minimac3, and the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and all available SNP genotypes across the six genes (mentioned above) implicated in previous genome-wide association studies was performed using logistic regression and assuming a log-additive model of inheritance.Of the six genomic regions examined, SNPs within the IKZF1, ARID5B, and PIP4K2A genes showed a statistically significant association with childhood ALL risk after Bonferroni correction. SNPs with the strongest evidence of association for these three genes included rs7090445 (ARID5B, OR=1.75, P =3.7x10-17), rs12533431 (IKZF1, OR=1.43, P =4.3x10-5), and rs11013045 (PIP4K2A, OR=0.76, P =9.5x10-5). Further examination of these regions indicated a second independently associated locus within ARID5B. Furthermore, we observed that the same previously reported primary ALL susceptibility SNPs for IKZF1 (e.g. rs4132601, rs11978267) and PIP4K2A (e.g. rs10828317, rs7088318) were not associated in Japanese. This highlights the importance of considering regional genetic variation comprehensively when testing the role of previously implicated candidate regions in a different racial/ethnic population. Characterization of the role of CEBPE, CDKN2A, and GATA3 genetic variation in Japanese may benefit from greater statistical power and potentially additional coverage of SNPs within these regions. DisclosuresNo relevant conflicts of interest to declare.

Genetic architecture of type 2 diabetes

Genome-wide association studies (GWAS) have identified over 70 loci associated with type 2 diabetes (T2D). Most genetic variants associated with T2D are common variants with modest effects on T2D and are shared with major ancestry groups. To what extent the genetic component of T2D can be explained by common variants relies upon the shape of the genetic architecture of T2D. Fine mapping utilizing populations with different patterns of linkage disequilibrium and functional annotation derived from experiments in relevant tissues are mandatory to track down causal variants responsible for the pathogenesis of T2D.

The USDA barley core collection: genetic diversity, population structure, and potential for genome-wide association studies.

New sources of genetic diversity must be incorporated into plant breeding programs if they are to continue increasing grain yield and quality, and tolerance to abiotic and biotic stresses. Germplasm collections provide a source of genetic and phenotypic diversity, but characterization of these resources is required to increase their utility for breeding programs. We used a barley SNP iSelect platform with 7,842 SNPs to genotype 2,417 barley accessions sampled from the USDA National Small Grains Collection of 33,176 accessions. Most of the accessions in this core collection are categorized as landraces or cultivars/breeding lines and were obtained from more than 100 countries. Both STRUCTURE and principal component analysis identified five major subpopulations within the core collection, mainly differentiated by geographical origin and spike row number (an inflorescence architecture trait). Different patterns of linkage disequilibrium (LD) were found across the barley genome and many regions of high LD contained traits involved in domestication and breeding selection. The genotype data were used to define ‘mini-core’ sets of accessions capturing the majority of the allelic diversity present in the core collection. These ‘mini-core’ sets can be used for evaluating traits that are difficult or expensive to score. Genome-wide association studies (GWAS) of ‘hull cover’, ‘spike row number’, and ‘heading date’ demonstrate the utility of the core collection for locating genetic factors determining important phenotypes. The GWAS results were referenced to a new barley consensus map containing 5,665 SNPs. Our results demonstrate that GWAS and high-density SNP genotyping are effective tools for plant breeders interested in accessing genetic diversity in large germplasm collections.

The Evaluation of Bovine SNP50 BeadChip Assay Performance in Polish Red Cattle Breed

According to increasing interest in the use of high density SNP (single nucleotide polymorphism) genotyping assays for genome-wide genetic studies in farm animals, there is a need to assess the usefulness of currently available genomic tools for application in different breeds. The performance of the assays may differ between the breeds because of discrepancies in allele frequencies of the polymorphisms or differences in linkage disequilibrium patterns. In this study we attempted to test the performance of the Bovine SNP50 v2 genotyping assay (Illumina) for population genetic and other applications in the Polish Red cattle breed. We found that 37,977 of the 53,438 autosomal markers included in the assay give high quality genomic information and can be used for different applications concerning this breed. The remaining markers were denoted as "of limited use" or redundant because of their weak performance, deviation from Hardy-Weinberg equilibrium, low minor allele frequency, high linkage disequilibrium with other neighboring markers or location on sex chromosomes.

Replication and fine mapping of asthma-associated loci in individuals of African ancestry.

Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.

Confounding and Heterogeneity in Genetic Association Studies with Admixed Populations

Association studies among admixed populations pose many challenges including confounding of genetic effects due to population substructure and heterogeneity due to different patterns of linkage disequilibrium (LD). We use simulations to investigate controlling for confounding by indicators of global ancestry and the impact of including a covariate for local ancestry. In addition, we investigate the use of an interaction term between a single-nucleotide polymorphism (SNP) and local ancestry to capture heterogeneity in SNP effects. Although adjustment for global ancestry can control for confounding, additional adjustment for local ancestry may increase power when the induced admixture LD is in the opposite direction as the LD in the ancestral population. However, if the induced LD is in the same direction, there is the potential for reduced power because of overadjustment. Furthermore, the inclusion of a SNP by local ancestry interaction term can increase power when there is substantial differential LD between ancestry populations. We examine these approaches in genome-wide data using the University of Southern California's Children's Health Study investigating asthma risk. The analysis highlights rs10519951 (P = 8.5 × 10(-7)), a SNP lacking any evidence of association from a conventional analysis (P = 0.5).

Genomic divergence of zebu and taurine cattle identified through high-density SNP genotyping

BackgroundNatural selection has molded evolution across all taxa. At an arguable date of around 330,000 years ago there were already at least two different types of cattle that became ancestors of nearly all modern cattle, the Bos taurus taurus more adapted to temperate climates and the tropically adapted Bos taurus indicus. After domestication, human selection exponentially intensified these differences. To better understand the genetic differences between these subspecies and detect genomic regions potentially under divergent selection, animals from the International Bovine HapMap Experiment were genotyped for over 770,000 SNP across the genome and compared using smoothed FST. The taurine sample was represented by ten breeds and the contrasting zebu cohort by three breeds.ResultsEach cattle group evidenced similar numbers of polymorphic markers well distributed across the genome. Principal components analyses and unsupervised clustering confirmed the well-characterized main division of domestic cattle. The top 1% smoothed FST, potentially associated to positive selection, contained 48 genomic regions across 17 chromosomes. Nearly half of the top FST signals (n = 22) were previously detected using a lower density SNP assay. Amongst the strongest signals were the BTA7:~50 Mb and BTA14:~25 Mb; both regions harboring candidate genes and different patterns of linkage disequilibrium that potentially represent intrinsic differences between cattle types. The bottom 1% of the smoothed FST values, potentially associated to balancing selection, included 24 regions across 13 chromosomes. These regions often overlap with copy number variants, including the highly variable region at BTA23:~24 Mb that harbors a large number of MHC genes. Under these regions, 318 unique Ensembl genes are annotated with a significant overrepresentation of immune related pathways.ConclusionsGenomic regions that are potentially linked to purifying or balancing selection processes in domestic cattle were identified. These regions are of particular interest to understand the natural and human selective pressures to which these subspecies were exposed to and how the genetic background of these populations evolved in response to environmental challenges and human manipulation.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-14-876) contains supplementary material, which is available to authorized users.