Low Linkage Disequilibrium Research Articles

Dissection of genetic variation and evidence for pleiotropy in male pattern baldness

Male pattern baldness (MPB) is a sex-limited, age-related, complex trait. We study MPB genetics in 205,327 European males from the UK Biobank. Here we show that MPB is strongly heritable and polygenic, with pedigree-heritability of 0.62 (SE = 0.03) estimated from close relatives, and SNP-heritability of 0.39 (SE = 0.01) from conventionally-unrelated males. We detect 624 near-independent genome-wide loci, contributing SNP-heritability of 0.25 (SE = 0.01), of which 26 X-chromosome loci explain 11.6%. Autosomal genetic variance is enriched for common variants and regions of lower linkage disequilibrium. We identify plausible genetic correlations between MPB and multiple sex-limited markers of earlier puberty, increased bone mineral density (rg = 0.15) and pancreatic β-cell function (rg = 0.12). Correlations with reproductive traits imply an effect on fitness, consistent with an estimated linear selection gradient of -0.018 per MPB standard deviation. Overall, we provide genetic insights into MPB: a phenotype of interest in its own right, with value as a model sex-limited, complex trait.

Associations of genetic variants in endocytic trafficking of epidermal growth factor receptor super pathway with risk of nonsyndromic cleft lip with or without cleft palate.

BackgroundThe genetic etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has not been fully clarified to date. Epidermal growth factor receptor (EGFR) was reportedly involved in its biological establishment and regulation of cell migration during the embryonic stage.MethodsWe selected a super pathway of endocytic trafficking of EGFR and investigated the associations of single‐nucleotide polymorphisms (SNPs) in the super pathway with the risk of NSCL/P by analyzing our published genome‐wide association study (GWAS) data from 504 NSCL/P individuals and 455 controls. After the false discovery rate (FDR) control, we conducted linkage disequilibrium (LD) analyses and conditional regression analyses to obtain independent lead SNPs. We performed LD analyses between the lead SNPs and the reported SNPs to find novel ones from our study. We annotated the lead SNPs and investigated their mapped genes in silico.ResultsA total of 82 SNPs showed a statistical association with the risk of NSCL/P after FDR control. They contained three reported SNPs which were g.117068049G>A (rs7078160), g.117086783C>G (rs10886040), and g.117101266G>T (rs17095681). Four independent lead SNPs were obtained, including g.116979803 T>C (rs1905539) and g.117037960A>G (rs7902502) at 10q25.3, g.35720163G>C (rs75656820) at 17q12, and g.156864512G>A (rs1800877) at 1q23.1. Three of them were in low LD (r 2 < 0.5) with the reported SNPs except g.117037960A>G (rs7902502), so these three were newly identified. Lead SNPs were mapped to three genes: SHTN1, AP2B1, and NTRK1. The three genes were relatively more highly expressed in the human craniofacial region and in the proximal maxillary location during the craniofacial development stage of the embryonic mouse.ConclusionOur results suggested that SHTN1, AP2B1, and NTRK1 might be associated with the development of NSCL/P.

Single-nucleotide polymorphisms(SNPs) in a sucrose synthase gene are associated with wood properties in Catalpa fargesii bur

BackgroundAssociation study is a powerful means for identifying molecular markers, such as single-nucleotide polymorphisms (SNPs) associated with important traits in forest trees. Catalpa fargesii Bur is a valuable commercial tree in China and identifying SNPs that associate with wood property would make a foundation of the marker-assisted breeding in the future. However, related work has not been reported yet.ResultsWe cloned a 2887 bp long sucrose synthase (SUS) gene from the genome of C. fargesii, which is a key enzyme in sucrose metabolism and also associated to wood formation in trees, coding 806 amino acids that expressed mainly in young branches, xylem, and leaves according to real-time quantitative PCR. Then we identified allelic variations of CfSUS associated with nine wood quality associated traits in Catalpa fargesii Bur. Totally, 135 SNPs were identified through cloning and sequencing the CfSUS locus from a mapping population (including 93 unrelated individuals) and 47 of which were genotyped as common SNPs (minor allele frequency > 5%) in the association population that comprised of 125 unrelated individuals collected from main distribution area. Nucleotide diversity and linkage disequilibrium (LD) analysis showed CfSUS has a relative low SNP diversity (πT = 0.0034) and low LD (r2 dropped below 0.1 within 1600 bp). Using the association analysis, we found 11 common SNPs and 14 haplotypes were significantly associated with the traits (false discovery rate, Q<0.1), explaining 3.21–12.41% of the phenotypic variance. These results provide molecular markers above associated with wood basic density, pore rate, and six other traits of wood, which have potential applications in breeding of Catalpa fargesii Bur.ConclusionWe first cloned a SUS gene in C. fargesii, then identified several SNPs and haplotypes that associated with wood properties within this gene, suggesting CfSUS participates in the wood formation of C. fargesii. Moreover, molecular markers we identified in this study may be applied into marker-assisted breeding of C. fargesii in the future.

Presencia de haplotipos no africanos incrementa la diversidad genética en pacientes con anemia falciforme en Colombia

El objetivo de este estudio fue identificar la frecuencia de haplotipos dentro del cluster de Beta globina presente en pacientes con anemia falciforme en Colombia, establecer la presencia de haplotipos no africanos en esta población, así como verificar variaciones en el patrón de desequilibrio de ligamiento dentro del cluster de Beta globina. Se analizaron 83 individuos con anemia falciforme, los haplotipos se formaron utilizando cinco sitios de restricción dentro del cluster de Beta globina, se estableció la frecuencia de haplotipos, se calculó el grado de desequilibrio de ligamiento entre los sitios de restricción, así como la similitud genética de esta población con otra de afectados en América. Los haplotipos más frecuentes en la población fueron Benín ( 35,1 %) y Bantú (26, 5 %), ambos africanos. Sin embargo, haplotipos presentes en poblaciones indígenas americanas y europeas alcanzaron frecuencias entre el 2 – 10 %, así como haplotipos que no han sido reportados en otras poblaciones. Los sitios de restricción presentaron bajo o nulo desequilibrio de ligamiento entre ellos. Al compararse con otras poblaciones, la población colombiana presentó mayor similitud con la población de Venezuela en donde Benin y Bantú son también predominantes. Nuestros resultados muestran que el mestizaje ha facilitado el paso de la mutación para la anemia falciforme a un contexto genético no africano (amerindio y europeo). Además, el mestizaje también ha alterado el patrón de desequilibrio de ligamiento dentro del cluster de Beta globina generando modificaciones que pueden tener influencia en estudios de asociación dentro de esta población de afectados.

Toll-like receptor 4 gene polymorphisms influence milk production traits in Chinese Holstein cows

The research reported in this Research Communication aimed to describe the influence of Toll-like receptor 4 gene polymorphisms on milk production traits in Chinese Holstein cows. Toll-like receptor 4 (TLR4) is an important member of the toll-like receptor gene family that is widely found in various organisms. Since TLR4 can identify molecular patterns from various pathogenic microorganisms and induce natural and acquired immunity, it plays an important role in disease resistance in dairy cows. Two single nucleotide polymorphisms (SNPs) of TLR4 (c.-226 G > C and c.2021 C > T) that were previously found to be associated with health traits were genotyped using Sequenom MassARRAY (Sequenom Inc., San Diego, CA) for Chinese Holstein cows (n = 866). The associations between SNPs or their haplotypes and milk production traits and somatic cell count were analyzed by the generalized linear model procedure of Statistics Analysis System software (SAS). The c.-226 G > C and c.2021 C > T showed low linkage disequilibrium (r2 = 0·192). There was no association between these two SNPs and SCC, but significant effects were found for SNP c.-226 G > C on test-day milk yield, fat content, protein content, and total solid and milk urea nitrogen (P T and the SNP haplotypes on test-day milk yield, fat content, protein content, lactose content and total solids (P C was located within several potential transcription factor binding sites, including transcription factor AP-2. The polymorphisms c.-226 G > C and c.2021 C > T had significant effects on the milk production for Chinese Holstein, and these SNP could be used for molecular marker-assisted selection of milk production.

Genetic Diversity and Molecular Characterization of Iranian Durum Wheat Landraces (Triticum turgidum durum (Desf.) Husn.) Using DArT Markers.

Durum wheat is grown mainly in rain-fed regions of Iran and the Mediterranean district under stressful conditions. Different environmental conditions and agricultural practices among ancient communities have led to the development of locally adapted genotypes known as landraces. Landraces are a valued source of genetic variety and show definite adaptation to local environmental conditions according to their home of origin. This study aimed to explore linkage disequilibrium (LD) analysis and the population structure and genetic diversity of Iranian durum wheat landraces. In this study, population structure and genome-wide LD were investigated in 129 durum landrace accessions using 1500 DArT markers. Both structure and discriminant analysis of principal components obviously subdivided the sample collection into seven distinct groups centered on key ancestors and regions of origin of the germplasm. Genetic diversity among the populations was primarily within population (68 vs. 32%). Mean LD values across the entire population sample decayed below r2 of 0.11 after 1cM. LD decay of genomes A and B of Iranian durum wheat landrace is approximately 2-3cM (r2 = 0.11) and approximately 0.5cM (r2 = 0.12), respectively. Altogether, low LD decay, a high number of subpopulations, and the high existence of genetic diversity among and within populations were characteristics of the Iranian durum landrace collection. Hence, the existing genetic diversity within the population can be associated with the very long evolutionary history of plants in Iran. The populations we studied are hence presented as a valuable resource that can be used in basic and applied research in durum wheat breeding.

Linkage Disequilibrium and Population Structure in Wild and Cultivated Populations of Rubber Tree (Hevea brasiliensis).

Among rubber tree species, which belong to the Hevea genus of the Euphorbiaceae family, Hevea brasiliensis (Willd. ex Adr.de Juss.) Muell. Arg. is the main commercial source of natural rubber production worldwide. Knowledge of the population structure and linkage disequilibrium (LD) of this species is essential for the efficient organization and exploitation of genetic resources. Here, we obtained single-nucleotide polymorphisms (SNPs) using a genotyping-by-sequencing (GBS) approach and then employed the SNPs for the following objectives: (i) to identify the positions of SNPs on a genetic map of a segregating mapping population, (ii) to evaluate the population structure of a germplasm collection, and (iii) to detect patterns of LD decay among chromosomes for future genetic association studies in rubber tree. A total of 626 genotypes, including both germplasm accessions (368) and individuals from a genetic mapping population (254), were genotyped. A total of 77,660 and 21,283 SNPs were detected by GBS in the germplasm and mapping populations, respectively. The mapping population, which was previously mapped, was constructed with 1,062 markers, among which only 576 SNPs came from GBS, reducing the average interval between two adjacent markers to 4.4 cM. SNPs from GBS genotyping were used for the analysis of genetic structure and LD estimation in the germplasm accessions. Two groups, which largely corresponded to the cultivated and wild populations, were detected using STRUCTURE and via principal coordinate analysis. LD analysis, also using the mapped SNPs, revealed that non-random associations varied along chromosomes, with regions of high LD interspersed with regions of low LD. Considering the length of the genetic map (4,693 cM) and the mean LD (0.49 for cultivated and 0.02 for wild populations), a large number of evenly spaced SNPs would be needed to perform genome-wide association studies in rubber tree, and the wilder the genotypes used, the more difficult the mapping saturation.

The impact of QTL allele frequency distribution on the accuracy of genomic prediction

Abstract. The accuracy of genomic prediction of quantitative traits based on single nucleotide polymorphism (SNP) markers depends among other factors on the allele frequency distribution of quantitative trait loci (QTL). Therefore, the aim of this study was to investigate different QTL allele frequency distributions and their effect on the accuracy of genomic estimated breeding values (GEBVs) using best linear unbiased genomic prediction (GBLUP) in simulated data. A population of 1000 individuals composed of 500 males and 500 females as well as a genome of 1000 cM consisting of 10 chromosomes and with a mutation rate of 2.5 × 10−5 per locus was simulated. QTL frequencies were derived from five distributions of allele frequency including constant, uniform, U-shaped, L-shaped and minor allele frequency (MAF) less than 0.01 (lowMAF). QTL effects were generated from a standard normal distribution. The number of QTL was assumed to be 500, and the simulation was done in 10 replications. The genomic prediction accuracy in the first-validation generation in constant, and the uniform allele frequency distribution was 0.59 and 0.57, respectively. Results showed that the highest accuracy of GEBVs was obtained with constant and uniform distributions followed by L-shaped, U-shaped and lowMAF QTL allele frequency distribution. The regression of true breeding values on predicted breeding values in the first-validation generation was 0.94, 0.92, 0.88, 0.85 and 0.75 for constant, uniform, L-shaped, U-shaped and lowMAF distributions, respectively. Depite different values of regression coefficients, in all scenarios GEBVs are biased downward. Overall, results showed that when QTL had a lower MAF relative to SNP markers, a low linkage disequilibrium (LD) was observed, which had a negative effect on the accuracy of GEBVs. Hence, the effect of the QTL allele frequency distribution on prediction accuracy can be alleviated through using a genomic relationship weighted by MAF or an LD-adjusted relationship matrix.

Genetic diversity of the Plasmodium vivax phosphatidylinositol 3-kinase gene in two regions of the China-Myanmar border

Artemisinin resistance in Plasmodium falciparum was associated with mutations in the propeller domain of the PfK13 gene and increased phosphatidylinositol-3′-kinase (PfPI3K) activity. Assessment of the genetic diversity of the PfK13 ortholog PvK12 in Plasmodium vivax field samples from the same hotspots of P. falciparum artemisinin resistance revealed a limited genetic diversity of PvK12. Following the same logic, we analyzed genetic variations of the PvPI3K gene in 188 P. vivax field isolates from two geographic locations along the China-Myanmar border. Overall, high genetic diversity of PvPI3K was observed; parasites from Yunnan's Tengchong County had higher genetic diversity than those from Laiza Township, Kachin State, Myanmar. Almost all the neutrality tests applied detected statistically significant deviation from zero. The negative Tajima's D values in both populations implicated that PvPI3K gene might have experienced either a directional selection or an expansion in population size. There was low linkage disequilibrium between the PvPI3K mutations in both populations, suggesting the existence of large, almost panmictic, parasite populations that enabled effective recombination. This later result was confirmed by the detection of a minimum of five recombination events in each population with two major breakpoints. Multiple tests for selection confirmed a signature of purifying selection on PvPI3K. All the amino acid mutations were predicted to be neutral for the PI3K protein's function. These findings provide insights on the genetic diversity of P. vivax populations along the China-Myanmar border.

Effect of genetic architecture on the prediction accuracy of quantitative traits in samples of unrelated individuals

Predicting complex phenotypes from genomic data is a fundamental aim of animal and plant breeding, where we wish to predict genetic merits of selection candidates; and of human genetics, where we wish to predict disease risk. While genomic prediction models work well with populations of related individuals and high linkage disequilibrium (LD) (e.g., livestock), comparable models perform poorly for populations of unrelated individuals and low LD (e.g., humans). We hypothesized that low prediction accuracies in the latter situation may occur when the genetics architecture of the trait departs from the infinitesimal and additive architecture assumed by most prediction models. We used simulated data for 10,000 lines based on sequence data from a population of unrelated, inbred Drosophila melanogaster lines to evaluate this hypothesis. We show that, even in very simplified scenarios meant as a stress test of the commonly used Genomic Best Linear Unbiased Predictor (G-BLUP) method, using all common variants yields low prediction accuracy regardless of the trait genetic architecture. However, prediction accuracy increases when predictions are informed by the genetic architecture inferred from mapping the top variants affecting main effects and interactions in the training data, provided there is sufficient power for mapping. When the true genetic architecture is largely or partially due to epistatic interactions, the additive model may not perform well, while models that account explicitly for interactions generally increase prediction accuracy. Our results indicate that accounting for genetic architecture can improve prediction accuracy for quantitative traits.

Association of elevated homocysteine levels and Methylenetetrahydrofolate reductase (MTHFR) 1298 A > C polymorphism with Vitiligo susceptibility in Gujarat

BackgroundSeveral studies have reported hyperhomocysteinemia in vitiligo patients, suggesting the potential role of elevated homocysteine levels in precipitating vitiligo. ObjectivesWe aimed to estimate homocysteine and vitamin B12 levels, and to investigate the role of MTHFR 677 C > T and 1298 A > C polymorphisms in vitiligo susceptibility in Gujarat population. MethodsHomocysteine and vitamin B12 levels were estimated in plasma of 55 vitiligo patients and 60 controls by Electrochemiluminescence immunoassay (ECLIA). Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) techniques were used to genotype MTHFR 677 C > T and 1298 A > C polymorphisms in 520 vitiligo patients and 558 controls. ResultsOur results showed significantly elevated homocysteine levels (p = 0.0003) as well as significant decrease in vitamin B12 levels (p = 0.0102) in vitiligo patients, as compared to controls. No significant difference in genotype and allele frequencies of MTHFR 677 C > T polymorphism was observed among patients and controls, however, the frequency of ‘CC’ genotype of MTHFR 1298 A > Cpolymorphism was significantly increased in patients as compared to controls (p = 0.0151). Analysis based on the type of vitiligo revealed a significant increase in ‘C’ allele of MTHFR 1298 A > C polymorphism in patients with generalized (p = 0.003) and active (p = 0.007) vitiligo as compared to controls. Both the polymorphisms of MTHFR were in low linkage disequilibrium (LD) and susceptible ‘TC’ haplotype was more frequently observed (p = 0.008) in vitiligo patients. Interestingly, elevated homocysteine levels were also positively correlated with MTHFR 1298 A > C polymorphism in vitiligo patients. Structure based in silico prediction revealed structural perturbations in MTHFR protein due to Ala222Val and Glu429Ala amino acid substitution. ConclusionsThe present findings suggest that MTHFR 1298 A > C polymorphism and, altered homocysteine and vitamin B12 levels might play a vital role in the precipitation of vitiligo.

Genomic analysis of family data reveals additional genetic effects on intelligence and personality

Pedigree-based analyses of intelligence have reported that genetic differences account for 50–80% of the phenotypic variation. For personality traits these effects are smaller, with 34–48% of the variance being explained by genetic differences. However, molecular genetic studies using unrelated individuals typically report a heritability estimate of around 30% for intelligence and between 0 and 15% for personality variables. Pedigree-based estimates and molecular genetic estimates may differ because current genotyping platforms are poor at tagging causal variants, variants with low minor allele frequency, copy number variants, and structural variants. Using ~20,000 individuals in the Generation Scotland family cohort genotyped for ~700,000 single-nucleotide polymorphisms (SNPs), we exploit the high levels of linkage disequilibrium (LD) found in members of the same family to quantify the total effect of genetic variants that are not tagged in GWAS of unrelated individuals. In our models, genetic variants in low LD with genotyped SNPs explain over half of the genetic variance in intelligence, education, and neuroticism. By capturing these additional genetic effects our models closely approximate the heritability estimates from twin studies for intelligence and education, but not for neuroticism and extraversion. We then replicated our finding using imputed molecular genetic data from unrelated individuals to show that ~50% of differences in intelligence, and ~40% of the differences in education, can be explained by genetic effects when a larger number of rare SNPs are included. From an evolutionary genetic perspective, a substantial contribution of rare genetic variants to individual differences in intelligence, and education is consistent with mutation-selection balance.

Trait Mapping Approaches Through Association Analysis in Plants.

Previously, association mapping (AM) methodology was used to unravel genetic complications in animal science by measuring the complex traits for candidate and non-candidate genes. Nowadays, this statistical approach is widely used to clarify the complexity in plant breeding program-based genome-wide breeding strategies, marker development, and diversity analysis. This chapter is particularly focused on methodologies with limitations and provides an overview of AM models and software used up to now. Association or linkage disequilibrium mapping has become a very popular method for discovering candidate and non-candidate genes and confirmation of quantitative trait loci (QTL) on various parts of the genome and in marker-assisted selection for breeding. Previously, various QTL investigations were carried out for different plants exclusively by linkage mapping. To help to understand the basics of modern molecular genetic techniques, in this chapter we summarize previous studies done on different crops. AM offers high-resolution power when there is large genotypic diversity and low linkage disequilibrium (LD) for the germplasm being investigated. The benefits of AM, compared with traditional QTL mapping, include a relatively detailed mapping resolution and a far less time-consuming approach since no mapping populations need to be generated. The advancements in genotyping and computational techniques have encouraged the use of AM. AM provides a fascinating approach for genetic investigation of QTLs, due to its resolution and the possibility to study the various genomic areas at the same time without construction of mapping populations. In this chapter we also discuss the advantages and disadvantages of AM, especially in the dicotyledonous crops Fabaceae and Solanaceae, with various genome-size reproductive strategies (clonal vs. sexual), and statistical models. The main objective of this chapter is to highlight the uses of association genetics in major and minor crop species that have trouble being analyzed for dissection of complex traits by identification of the factor responsible for controlling the effect of trait. Graphical Abstract.

Lessons from ten years of genome-wide association studies of asthma.

Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10−8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.

Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: Independent and IL-6-interactive associations.

Interleukin-6 (IL-6) induces the expression of fibrinogen, and polymorphic variation within the fibrinogen genes is believed to alter the magnitude of this expression. The identification of the functional relevance of individual fibrinogen single nucleotide polymorphisms (SNPs) has been hindered by the high linkage disequilibrium (LD) reported in the European fibrinogen gene locus. This study investigated two novel and 12 known fibrinogen SNPs of potential functional relevance, in 2010 Tswana individuals known to have low LD. We aimed to identify functional polymorphisms that contribute to clot-related phenotypes and total and γ’ fibrinogen concentrations independently and through their interaction with IL-6, by taking advantage of the high fibrinogen and IL-6 concentrations and the low LD reported in black South Africans. Fibrinogen was significantly associated with IL-6, thereby mediating associations of IL-6 with clot formation and structure, although attenuating the association of IL-6 with clot lysis time. None of the common European fibrinogen haplotypes was present in this study population. Putative functional fibrinogen SNPs FGB–rs7439150, rs1800789 (–1420G/A) and rs1800787 (–148C/T) were significantly associated with fibrinogen concentration and altered clot properties, with several associations significantly influenced by IL-6 concentrations. The impact of harbouring several minor fibrinogen SNP alleles on the association of IL-6 and fibrinogen concentration was cumulative, with possession of each additional minor allele showing a stronger relationship of IL-6 with fibrinogen. This was also reflected in differences in clot properties, suggesting potential clinical relevance. Therefore, when investigating the effect of fibrinogen genetics on fibrinogen concentrations and CVD outcome, the possible interactions with modulating factors and the fact that SNP effects seem to be additive should be taken into account.

Genetic mapping using 1.4M SNP array refined loci for fatty acid composition traits in Chinese Erhualian and Bamaxiang pigs.

Chinese indigenous pigs display marked genetic and phenotypic differences compared with western commercial pigs. In this study, we tested the association between 660K SNPs and longissimus muscle fatty acid composition traits in Chinese Erhualian (n=331) and Bamaxiang (n=315) pigs based on a customized 1.4 million SNP array. We identified a total of 64 significant associations for 20 fatty acid composition traits at the p-value threshold of 1×10-6 among which 42 associations in low linkage disequilibrium (r2 <.2) with previously reported loci were considered novel. We substantially improved the strength and precision of the associations at four previously detected loci near FADS2, ELOVL7, ELOVL6 and FASN genes, facilitating follow-up candidate gene studies. Moreover, we also identified loci near ABCD2, ACSBG1, ELOVL5, HPGDS, DAGT2, ACAD10 and ACSL1 genes with function relevant to metabolism of fatty acids. In this study, valuable genetic variants and candidate genes associated with fatty acid composition traits were identified in Erhualian and Bamaxiang pigs. Some identified loci could be used to improve pork nutrition in pig breeding practice. Using the SNP array with higher marker density and less ascertainment bias improved QTL detection power and precision in Chinese indigenous pigs.

Is there an optimum level of diversity in utilization of genetic resources?

Key messageCapitalizing upon the genomic characteristics of long-term random mating populations, sampling from pre-selected landraces is a promising approach for broadening the genetic base of elite germplasm for quantitative traits.Genome-enabled strategies for harnessing untapped allelic variation of landraces are currently evolving. The success of such approaches depends on the choice of source material. Thus, the analysis of different strategies for sampling allelic variation from landraces and their impact on population diversity and linkage disequilibrium (LD) is required to ensure the efficient utilization of diversity. We investigated the impact of different sampling strategies on diversity parameters and LD based on high-density genotypic data of 35 European maize landraces each represented by more than 20 individuals. On average, five landraces already captured ~95% of the molecular diversity of the entire dataset. Within landraces, absence of pronounced population structure, consistency of linkage phases and moderate to low LD levels were found. When combining data of up to 10 landraces, LD decay distances decreased to a few kilobases. Genotyping 24 individuals per landrace with 5k SNPs was sufficient for obtaining representative estimates of diversity and LD levels to allow an informed pre-selection of landraces. Integrating results from European with Central and South American landraces revealed that European landraces represent a unique and diverse spectrum of allelic variation. Sampling strategies for harnessing allelic variation from landraces depend on the study objectives. If the focus lies on the improvement of elite germplasm for quantitative traits, we recommend sampling from pre-selected landraces, as it yields a wide range of diversity, allows optimal marker imputation, control for population structure and avoids the confounding effects of strong adaptive alleles.

Genomic prediction by considering genotype × environment interaction using different genomic architectures

Abstract In this study, accuracies of genomic prediction across various scenarios were compared using single- trait and multiple-trait animal models to detect genotype × environment (G × E) interaction based on REML method. The simulated high and low linkage disequilibrium (HLD and LLD) genome consisted of 15,000 and 50,000 SNP chip applications with 300 and 600 QTLs controlling the trait of interest. The simulation was done to create the genetic correlations between the traits in 4 environments and heritabilities of the traits were 0.20, 0.25, 0.30 and 0.35 in environments 1, 2, 3 and 4, respectively. Two strategies were used to predict the accuracy of genomic selection for cows without phenotypes. In the first strategy, phenotypes for cows in three environments were kept as a training set and breeding values for all animals were estimated using three-trait model. In the second one, only 25, 50 or 75% of records in the fourth environment and all the records in the other three environments were used to predict GBV for non-phenotyped cows in the environment 4. For the first strategy, the highest accuracy of 0.695 was realized in scenario HLD with 600 QTL and 50K SNP chip for the fourth environment and the lowest accuracy of 0.495 was obtained in scenario LLD with 600QTL and 15K SNP chips for the first environment. Generally, the accuracy of prediction increased significantly (P&lt;0.05) with increasing the number of markers, heritability and the genetic correlation between the traits, but no significant difference was observed between scenarios with 300 and 600 QTL. In comparison with models without G × E interaction, accuracies of the GBV for all environments increased when using multi-trait models. The results showed that the level of LD, number of animals in training set and genetic correlation across environments play important roles if G × E interaction exists. In conclusion, G × E interaction contributes to understanding variations of quantitative trait and increasing accuracy of genomic prediction. Therefore, the interaction should be taken into account in conducting selection in various environments or across different genotypes.

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Genome-wide association analysis for chronic venous disease identifies EFEMP1 and KCNH8 as susceptibility loci

Chronic venous disease (CVD) is a multifactorial condition representing one of the most common disorders among populations of Western countries. The heritability of about 17% suggests genetic risk factors in CVD etiology. However, so far the genetic causes are unknown. We undertook the hitherto first genome-wide association study (GWAS) for CVD, analyzing more than 1.93 M SNPs in 4,942 German individuals, followed by replication in two independent German data sets. The combined analysis of discovery and replication stages (2,269 cases and 7,765 controls) yielded robust associations within the two genes EFEMP1 and KCNH8 (rs17278665, rs727139 with P < 5 × 10−8), and suggestive association within gene SKAP2 (rs2030136 with P < 5 × 10−7). Association signals of rs17278665 and rs727139 reside in regions of low linkage disequilibrium containing no other genes. Data from the ENCODE and Roadmap Epigenomics projects show that tissue specific marks overlap with the variants. SNPs rs17278665 and rs2030136 are known eQTLs. Our study demonstrates that GWAS are a valuable tool to study the genetic component of CVD. With our approach, we identified two novel genome-wide significant susceptibility loci for this common disease. Particularly, the extracellular matrix glycoprotein EFEMP1 is promising for future functional studies due to its antagonistic role in vessel development and angiogenesis.