Haplotype-Based Single-Step GWAS for Yearling Temperament in American Angus Cattle

Behavior is a complex trait and, therefore, understanding its genetic architecture is paramount for the development of effective breeding strategies. The objective of this study was to perform traditional and weighted single-step genome-wide association studies (ssGWAS and WssGWAS, respectively) for yearling temperament (YT) in North American Angus cattle using haplotypes. Approximately 266 K YT records and 70 K animals genotyped using a 50 K single nucleotide polymorphism (SNP) panel were used. Linkage disequilibrium thresholds (LD) of 0.15, 0.50, and 0.80 were used to create the haploblocks, and the inclusion of non-LD-clustered SNPs (NCSNP) with the haplotypes in the genomic models was also evaluated. WssGWAS did not perform better than ssGWAS. Cattle YT was found to be a highly polygenic trait, with genes and QTL broadly distributed across the whole genome. Association studies using LD-based haplotypes should include NCSNPs and different LD thresholds to increase the likelihood of finding the relevant genomic regions affecting the trait of interest. The main candidate genes identified, i.e., ATXN10, ADAM10, VAX2, ATP6V1B1, CRISPLD1, CAPRIN1, FA2H, SPEF2, PLXNA1, and CACNA2D3, are involved in important biological processes and metabolic pathways related to behavioral traits, social interactions, and aggressiveness in cattle. Future studies should further investigate the role of these genes.

Approaching Genetics Through the MHC Lens: Tools and Methods for HLA Research

The current SARS-CoV-2 pandemic era launched an immediate and broad response of the research community with studies both about the virus and host genetics. Research in genetics investigated HLA association with COVID-19 based on in silico, population, and individual data. However, they were conducted with variable scale and success; convincing results were mostly obtained with broader whole-genome association studies. Here, we propose a technical review of HLA analysis, including basic HLA knowledge as well as available tools and advice. We notably describe recent algorithms to infer and call HLA genotypes from GWAS SNPs and NGS data, respectively, which opens the possibility to investigate HLA from large datasets without a specific initial focus on this region. We thus hope this overview will empower geneticists who were unfamiliar with HLA to run MHC-focused analyses following the footsteps of the Covid-19|HLA & Immunogenetics Consortium.

Robust Performance of Potentially Functional SNPs in Machine Learning Models for the Prediction of Atorvastatin-Induced Myalgia

Background:Statins can cause muscle symptoms resulting in poor adherence to therapy and increased cardiovascular risk. We hypothesize that combinations of potentially functional SNPs (pfSNPs), rather than individual SNPs, better predict myalgia in patients on atorvastatin. This study assesses the value of potentially functional single nucleotide polymorphisms (pfSNPs) and employs six machine learning algorithms to identify the combination of SNPs that best predict myalgia.Methods: Whole genome sequencing of 183 Chinese, Malay and Indian patients from Singapore was conducted to identify genetic variants associated with atorvastatin induced myalgia. To adjust for confounding factors, demographic and clinical characteristics were also examined for their association with myalgia. The top factor, sex, was then used as a covariate in the whole genome association analyses. Variants that were highly associated with myalgia from this and previous studies were extracted, assessed for potential functionality (pfSNPs) and incorporated into six machine learning models. Predictive performance of a combination of different models and inputs were compared using the average cross validation area under ROC curve (AUC). The minimum combination of SNPs to achieve maximum sensitivity and specificity as determined by AUC, that predict atorvastatin-induced myalgia in most, if not all the six machine learning models was determined.Results: Through whole genome association analyses using sex as a covariate, a larger proportion of pfSNPs compared to non-pf SNPs were found to be highly associated with myalgia. Although none of the individual SNPs achieved genome wide significance in univariate analyses, machine learning models identified a combination of 15 SNPs that predict myalgia with good predictive performance (AUC >0.9). SNPs within genes identified in this study significantly outperformed SNPs within genes previously reported to be associated with myalgia. pfSNPs were found to be more robust in predicting myalgia, outperforming non-pf SNPs in the majority of machine learning models tested.Conclusion: Combinations of pfSNPs that were consistently identified by different machine learning models to have high predictive performance have good potential to be clinically useful for predicting atorvastatin-induced myalgia once validated against an independent cohort of patients.

Multi-Parental Populations Suitable for Identifying Sources of Resistance to Powdery Mildew in Winter Wheat

Wheat (Triticum aestivum L.) is one of the world’s staple food crops and one of the most devastating foliar diseases attacking wheat is powdery mildew (PM). In Denmark only a few specific fungicides are available for controlling PM and the use of resistant cultivars is often recommended. In this study, two Chinese wheat landraces and two synthetic hexaploid wheat lines were used as donors for creating four multi-parental populations with a total of 717 individual lines to identify new PM resistance genetic variants. These lines and the nine parental lines (including the elite cultivars used to create the populations) were genotyped using a 20 K Illumina SNP chip, which resulted in 8,902 segregating single nucleotide polymorphisms for assessment of the population structure and whole genome association study. The largest genetic difference among the lines was between the donors and the elite cultivars, the second largest genetic difference was between the different donors; a difference that was also reflected in differences between the four multi-parental populations. The 726 lines were phenotyped for PM resistance in 2017 and 2018. A high PM disease pressure was observed in both seasons, with severities ranging from 0 to >50%. Whole genome association studies for genetic variation in PM resistance in the populations revealed significant markers mapped to either chromosome 2A, B, or D in each of the four populations. However, linkage disequilibrium between these putative quantitative trait loci (QTL) were all above 0.80, probably representing a single QTL. A combined analysis of all the populations confirmed this result and the most associated marker explained 42% of the variation in PM resistance. This study gives both knowledge about the resistance as well as molecular tools and plant material that can be utilised in marker-assisted selection. Additionally, the four populations produced in this study are highly suitable for association studies of other traits than PM resistance.

A Sardinian founder mutation in GP1BB that impacts thrombocytopenia

To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17×10−16). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13×10−10), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10−8) and GPIX (−24.69%, P=2.66×10−6). Molecular modeling infers a corresponding reduction in the stability of GP1BB. These observations predict that in homozygosity as well as in individuals carrying specific compound heterozygous configurations, this variant likely causes BSS.