Weak LD Research Articles

Haplotype-tagged SNPs improve genomic prediction accuracy for Fusarium head blight resistance and yield-related traits in wheat

Key messageLinkage disequilibrium (LD)-based haplotyping with subsequent SNP tagging improved the genomic prediction accuracy up to 0.07 and 0.092 for Fusarium head blight resistance and spike width, respectively, across six different models.Genomic prediction is a powerful tool to enhance genetic gain in plant breeding. However, the method is accompanied by various complications leading to low prediction accuracy. One of the major challenges arises from the complex dimensionality of marker data. To overcome this issue, we applied two pre-selection methods for SNP markers viz. LD-based haplotype-tagging and GWAS-based trait-linked marker identification. Six different models were tested with preselected SNPs to predict the genomic estimated breeding values (GEBVs) of four traits measured in 419 winter wheat genotypes. Ten different sets of haplotype-tagged SNPs were selected by adjusting the level of LD thresholds. In addition, various sets of trait-linked SNPs were identified with different scenarios from the training-test combined and only from the training populations. The BRR and RR-BLUP models developed from haplotype-tagged SNPs had a higher prediction accuracy for FHB and SPW by 0.07 and 0.092, respectively, compared to the corresponding models developed without marker pre-selection. The highest prediction accuracy for SPW and FHB was achieved with tagged SNPs pruned at weak LD thresholds (r2 < 0.5), while stringent LD was required for spike length (SPL) and flag leaf area (FLA). Trait-linked SNPs identified only from training populations failed to improve the prediction accuracy of the four studied traits. Pre-selection of SNPs via LD-based haplotype-tagging could play a vital role in optimizing genomic selection and reducing genotyping costs. Furthermore, the method could pave the way for developing low-cost genotyping methods through customized genotyping platforms targeting key SNP markers tagged to essential haplotype blocks.

Stochastic equations with time-dependent singular drift

We prove unique weak solvability for stochastic differential equations with drift in a large class of time-dependent vector fields. This class contains, in particular, the critical Ladyzhenskaya-Prodi-Serrin class, the weak Ld class as well as some vector fields that are not even in Lloc2+ε, ε>0.

Genetic Predictors of Type 2 Diabetes in Yakuts

The goal of this study was to investigate the distribution of alleles and genotypes of the KCNJ11 rs5219, PPARG rs1801282, TCF7L2 rs7903146/rs12255372 SNPs in Yakuts with T2D, in comparison with other ethnic populations. Methods and Results: The study cohort consisted of 26 Yakut patients diagnosed with T2D (YKT2D). Genotyping of rs5219 (KCNJ11), rs1801282 (PPARG), rs7903146 and rs12255372 (TCF7L2) SNPs was performed by pyrosequencing using PyroMark Q48 Autoprep sequencer (QIAGEN). The genotyping of the studied group of Yakuts did not reveal statistically significant differences between control groups and YKT2D patients with respect to the polymorphic variants of the KCNJ11, PPARG, and TCF7L2 genes. The allele frequency analysis of the polymorphisms of the KCNJ11, PPARG, and TCF7L2 genes demonstrated a low frequency of the risk T-allele in the TCF7L2 (rs7903146, rs12255372) in Asian populations, compared to other human populations. We identified three haplotypes [CG (90.5%), TT (6.8%), and TG (2.7%)] in the YKT2D cohort. Also, we observed a strong LD between two SNPs (rs7903146 and rs12255372) of the TCF7L2 gene in the majority of groups, including YKT2D (D '= 1, LOD = 4.92), except for African populations, where a very weak LD (D '= 0.001-0.435, LOD = 0.0-0.73) was observed.

Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Assessment of genetic diversity and population structure in cultured Australian Pacific oysters.

The recent development of Pacific oyster (Crassostrea gigas) SNP genotyping arrays has allowed detailed characterisation of genetic diversity and population structure within and between oyster populations. It also raises the potential of harnessing genomic selection for genetic improvement in oyster breeding programmes. The aim of this study was to characterise a breeding population of Australian oysters through genotyping and analysis of 18027 SNPs, followed by comparison with genotypes of oyster sampled from Europe and Asia. This revealed that the Australian populations had similar population diversity (HE ) to oysters from New Zealand, the British Isles, France and Japan. Population divergence was assessed using PCA of genetic distance and revealed that Australian oysters were distinct from all other populations tested. Australian Pacific oysters originate from planned introductions sourced from three Japanese populations. Approximately 95% of these introductions were from geographically, and potentially genetically, distinct populations from the Nagasaki oysters assessed in this study. Finally, in preparation for the application of genomic selection in oyster breeding programmes, the strength of LD was evaluated and subsets of loci were tested for their ability to accurately infer relationships. Weak LD was observed on average; however, SNP subsets were shown to accurately reconstitute a genomic relationship matrix constructed using all loci. This suggests that low-density SNP panels may have utility in the Australian population tested, and the findings represent an important first step towards the design and implementation of genomic approaches for applied breeding in Pacific oysters.

Brownian motion with general drift

We construct and study the weak solution to stochastic differential equation dX(t)=−b(X(t))dt+2dW(t), X(0)=x, for every x∈Rd, d≥3, with b in the class of weakly form-bounded vector fields, containing, as proper subclasses, a sub-critical class [Ld+L∞]d, as well as critical classes such as weak Ld class, Kato class, Campanato–Morrey class.

Sign of a perturbed massive Dirac operator and associated Fredholm module

We provide an algorithm to compute the sign of the massive Dirac operator Dm,m>0, on Rd,d≥2, perturbed by an electromagnetic potential V, modulo weak Schatten ideal Lp,∞ for arbitrarily small p>0. As a corollary, we prove a necessary and sufficient condition for the quantised derivative i[sgn(Dm+V),1⊗Mf] of a bounded function f on Rd to belong to the weak Schatten ideal Ld,∞.

Impact of the IL-17F, IL-23 and IL-23R on susceptibility and phenotype of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease characterized by excessive proinflammatory cytokine production and damage to multiple organ systems. To investigate the potential association between cytokine gene polymorphisms and SLE, we performed a case-control study based on Polish population. SLE patients and controls, were examined for IL-23A rs11171806 G/A and IL-23R (rs1884444 G/T, rs10489629 G/A) by TaqMan SNP genotyping assay, for IL-17F rs763780 A/G and rs2397084A/G using the PCR– RFLP method. An increased frequency of AG genotype as well as G allele of the IL-17F rs763780 was found in patients with SLE, as compared with healthy subjects (OR = 3.947; p = 0.001 and OR = 3.538; p = 0.002, respectively). Frequencies of the rs1884444 TT genotype (OR = 138.1) and the rs1884444 T allele (OR = 2.176) were also higher in SLE patients (both p < 0.0001). Overall, weak LD was observed between the IL-17F rs763780 A/G and rs2397084 A/G polymorphisms (D'-0.003, r2 – 0.000). From four possible haplotypes, frequencies of AG showed differences between both examined groups (p < 0.0001). We also observed a weak LD between the IL-23R rs10489629G/A and rs1884444 G/T (D'-0.199, r2 –0.026). The genotype–phenotype analysis showed significant association between the IL-17F rs2397084 and mean value of the hemoglobin (p = 0.01), the IL-17F rs763780 and age (p = 0.008) and lupus anticoagulant (p = 0.09), the IL-23 rs11171806 and urea (p = 0.08) and C3 complement (p = 0.03), and the IL-23R rs1884444 G/T and activated partial thromboplastin time (p = 0.06). Present findings indicated that IL-17F rs763780 A/G and IL-23R rs1884444 G/T polymorphisms may be involved in susceptibility to SLE in the Polish population.

Genome Wide Association Studies (GWAS) Identify QTL on SSC2 and SSC17 Affecting Loin Peak Shear Force in Crossbred Commercial Pigs.

Of all the meat quality traits, tenderness is considered the most important with regard to eating quality and market value. In this study we have utilised genome wide association studies (GWAS) for peak shear force (PSF) of loin muscle as a measure of tenderness for 1,976 crossbred commercial pigs, genotyped for 42,721 informative SNPs using the Illumina PorcineSNP60 Beadchip. Four 1 Mb genomic regions, three on SSC2 (at 4 Mb, 5 Mb and 109 Mb) and one on SSC17 (at 20 Mb), were detected which collectively explained about 15.30% and 3.07% of the total genetic and phenotypic variance for PSF respectively. Markers ASGA0008566, ASGA0008695, DRGA0003285 and ASGA0075615 in the four regions were strongly associated with the effects. Analysis of the reference genome sequence in the region with the most important SNPs for SSC2_5 identified FRMD8, SLC25A45 and LTBP3 as potential candidate genes for meat tenderness on the basis of functional annotation of these genes. The region SSC2_109 was close to a previously reported candidate gene CAST; however, the very weak LD between DRGA0003285 (the best marker representing region SSC2_109) and CAST indicated the potential for additional genes which are distinct from, or interact with, CAST to affect meat tenderness. Limited information of known genes in regions SSC2_109 and SSC17_20 restricts further analysis. Re-sequencing of these regions for informative animals may help to resolve the molecular architecture and identify new candidate genes and causative mutations affecting this trait. These findings contribute significantly to our knowledge of the genomic regions affecting pork shear force and will potentially lead to new insights into the molecular mechanisms regulating meat tenderness.

Imputation without doing imputation: a new method for the detection of non-genotyped causal variants.

Genome-wide association studies allow detection of non-genotyped disease-causing variants through testing of nearby genotyped SNPs. This approach may fail when there are no genotyped SNPs in strong LD with the causal variant. Several genotyped SNPs in weak LD with the causal variant may, however, considered together, provide equivalent information. This observation motivates popular but computationally intensive approaches based on imputation or haplotyping. Here we present a new method and accompanying software designed for this scenario. Our approach proceeds by selecting, for each genotyped “anchor” SNP, a nearby genotyped “partner” SNP, chosen via a specific algorithm we have developed. These two SNPs are used as predictors in linear or logistic regression analysis to generate a final significance test. In simulations, our method captures much of the signal captured by imputation, while taking a fraction of the time and disc space, and generating a smaller number of false-positives. We apply our method to a case/control study of severe malaria genotyped using the Affymetrix 500K array. Previous analysis showed that fine-scale sequencing of a Gambian reference panel in the region of the known causal locus, followed by imputation, increased the signal of association to genome-wide significance levels. Our method also increases the signal of association from to . Our method thus, in some cases, eliminates the need for more complex methods such as sequencing and imputation, and provides a useful additional test that may be used to identify genetic regions of interest.

Weak type inequalities for the ℓ 1-summability of higher dimensional Fourier transforms

Under some weak conditions on θ, it was verified in [21, 17] that the maximal operator of the l1-θ-means of a tempered distribution is bounded from Hp(ℝd) to Lp(ℝd) for all d/(d + α) < p ≤ ∞, where 0 < α ≤ 1 depends only on θ. In this paper, we prove that the maximal operator is bounded from Hd/(d+α)(ℝd) to the weak Ld/(d+α)(ℝd) space. The analogous result is given for Fourier series, as well. Some special cases of the l1-θ-summation are considered, such as the Weierstrass, Picard, Bessel, Fejer, de La Vallee-Poussin, Rogosinski and Riesz summations.

Abstract 2546: Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression.

Abstract We have previously reported an association between prostate cancer (PrCa) risk and rs2242652 on 5p15. rs2242652 lies in intron 4 of TERT, which encodes telomerase reverse transcriptase, the catalytic subunit of the telomerase ribonucleoprotein complex. Telomerase catalyzes the de novo addition of telomere repeat sequences on to chromosome ends and thereby counterbalances telomere-dependent replicative senescence. Associations between SNPs in the TERT region and multiple cancer types have been reported; however no correlation has been observed thus far between the cancer-associated SNPs in TERT and gene expression or telomere length. To comprehensively evaluate the association between genetic variation across this region and PrCa we performed a fine-mapping analysis by direct genotyping using either a custom Illumina iSelect array (114 SNPs on iCOGS) or Sequenom MassArray iPlex (25 SNPs) followed by imputation of 1,094 SNPs in 22,301 PrCa cases and 22,320 controls in the PRACTICAL consortium. To determine independently associated variants in this region, we performed multiple stepwise logistic regression analysis; SNPs were included in the model if they were significant at P&amp;lt;10−4 after adjustment for other SNPs. Regression models identified multiple independent associations, reflecting the complexity of this region. These SNPs fall into four regions consisting of clusters of highly or moderately correlated variants, and there is only weak LD between SNPs in different regions. To investigate whether SNPs in any of these regions were associated with TERT gene expression, we performed qPCR assays on RNA from benign prostate tissue samples using the Fluidigm Biomark™ HD system. We found evidence that the risk reducing alleles of several variants in region one associated with elevated TERT expression, providing a plausible mechanism for the differential effect of SNPs on PrCa risk. Deep re-sequencing of these loci may help to further refine this region and facilitate selection of prospective causal variants for functional validation studies. Citation Format: Zsofia Kote-Jarai, Edward Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Tokhir Dadaev, Sarah Jugurnauth, Sara Benlloch, Ali Amin Al Olama, Helen Ross-Adams, David Neal, The UKGPCS Collaborators and The PRACTICAL Consortium, Douglas Easton, Rosalind Eeles. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2013-2546

A genome-wide association study of serum uric acid in African Americans

BackgroundUric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI), sex, and multiple complex diseases including gout, hypertension (HTN), renal disease, and type 2 diabetes (T2D). Multiple genome-wide association studies (GWAS) in individuals of European ancestry (EA) have reported associations between serum uric acid levels (SUAL) and specific genomic loci. The purposes of this study were: 1) to replicate major signals reported in EA populations; and 2) to use the weak LD pattern in African ancestry population to better localize (fine-map) reported loci and 3) to explore the identification of novel findings cognizant of the moderate sample size.MethodsAfrican American (AA) participants (n = 1,017) from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix® Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs) were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification.ResultsFour variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 × 10-9 to 1.38 × 10-9). Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples.ConclusionsThe most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA populations GWAS signals in African-ancestry populations with weaker linkage disequilibrium.

Accuracy of genome-wide imputation of untyped markers and impacts on statistical power for association studies

BackgroundAlthough high-throughput genotyping arrays have made whole-genome association studies (WGAS) feasible, only a small proportion of SNPs in the human genome are actually surveyed in such studies. In addition, various SNP arrays assay different sets of SNPs, which leads to challenges in comparing results and merging data for meta-analyses. Genome-wide imputation of untyped markers allows us to address these issues in a direct fashion.Methods384 Caucasian American liver donors were genotyped using Illumina 650Y (Ilmn650Y) arrays, from which we also derived genotypes from the Ilmn317K array. On these data, we compared two imputation methods: MACH and BEAGLE. We imputed 2.5 million HapMap Release22 SNPs, and conducted GWAS on ~40,000 liver mRNA expression traits (eQTL analysis). In addition, 200 Caucasian American and 200 African American subjects were genotyped using the Affymetrix 500 K array plus a custom 164 K fill-in chip. We then imputed the HapMap SNPs and quantified the accuracy by randomly masking observed SNPs.ResultsMACH and BEAGLE perform similarly with respect to imputation accuracy. The Ilmn650Y results in excellent imputation performance, and it outperforms Affx500K or Ilmn317K sets. For Caucasian Americans, 90% of the HapMap SNPs were imputed at 98% accuracy. As expected, imputation of poorly tagged SNPs (untyped SNPs in weak LD with typed markers) was not as successful. It was more challenging to impute genotypes in the African American population, given (1) shorter LD blocks and (2) admixture with Caucasian populations in this population. To address issue (2), we pooled HapMap CEU and YRI data as an imputation reference set, which greatly improved overall performance. The approximate 40,000 phenotypes scored in these populations provide a path to determine empirically how the power to detect associations is affected by the imputation procedures. That is, at a fixed false discovery rate, the number of cis-eQTL discoveries detected by various methods can be interpreted as their relative statistical power in the GWAS. In this study, we find that imputation offer modest additional power (by 4%) on top of either Ilmn317K or Ilmn650Y, much less than the power gain from Ilmn317K to Ilmn650Y (13%).ConclusionCurrent algorithms can accurately impute genotypes for untyped markers, which enables researchers to pool data between studies conducted using different SNP sets. While genotyping itself results in a small error rate (e.g. 0.5%), imputing genotypes is surprisingly accurate. We found that dense marker sets (e.g. Ilmn650Y) outperform sparser ones (e.g. Ilmn317K) in terms of imputation yield and accuracy. We also noticed it was harder to impute genotypes for African American samples, partially due to population admixture, although using a pooled reference boosts performance. Interestingly, GWAS carried out using imputed genotypes only slightly increased power on top of assayed SNPs. The reason is likely due to adding more markers via imputation only results in modest gain in genetic coverage, but worsens the multiple testing penalties. Furthermore, cis-eQTL mapping using dense SNP set derived from imputation achieves great resolution, and locate associate peak closer to causal variants than conventional approach.

Family study of linkage disequilibrium between TAP2 transporter and HLA class II genes absence of TAP2 contribution to association with insulin-dependent diabetes mellitus

The polymorphic TAP1 and TAP2 genes encode a transporter protein required for delivery of cytosolic peptides to class I molecules in the endoplasmic reticulum. Associations have been observed between TAP2 alleles and predisposition to autoimmune diseases such as IDDM but their interpretation has been complicated by the existence of LD between TAP2 and HLA class II loci, and conclusions are still contradictory. In order to precisely define LD on class II haplotypes, we performed an extensive familial analysis. A total of 466 individuals from 55 normal families and 49 IDDM multiplex families was studied, providing information on 420 independent haplotypes. The IDDM-predisposing DRB1 ∗03 and DRB1 ∗04 alleles were in strong negative LD with TAP2-B ( Δ = −0.035 and −0.034, respectively), and positive LD with TAP2-A ( Δ = +0.055 and + 0.012). Positive LD was also found between TAP2-B and DRB1 ∗01 and TAP2-C and DRB1 ∗11 alleles. We then addressed the question of whether TAP2 is an independent additional IDDM-protective or predisposing genetic factor. No TAP2 effect was evidenced when considering DRB1 ∗03 and/or 04 patients. A decreased TAP2-B phenotype frequency was observed in DRB1 ∗03- and DRB1 ∗04-negative IDDM patients compared with DRB1 ∗03- and DRB1*04-negative normal controls (38.6% vs 63%, p C < 0.05), but was probably related to a combination of different weak LD between DRB1 and TAP2 alleles. It thus appears that there is no primary association between TAP2 alleles and IDDM. However, TAP polymorphism may allow us to define particular extended HLA haplotypes involved in susceptibility to autoimmune diseases.

Reconsideration of genetic mapping of the weak LD locus.

Reconsideration of genetic mapping of the weak LD locus.