Characterizing rare and low-frequency height-associated variants in the Japanese population

Abstract Human height is a representative phenotype to elucidate genetic architecture. However, the majority of large studies have been performed in European population. To investigate the rare and low-frequency variants associated with height, we construct a reference panel (N = 3,541) for genotype imputation by integrating the whole-genome sequence data from 1,037 Japanese with that of the 1000 Genomes Project, and perform a genome-wide association study in 191,787 Japanese. We report 573 height-associated variants, including 22 rare and 42 low-frequency variants. These 64 variants explain 1.7% of the phenotypic variance. Furthermore, a gene-based analysis identifies two genes with multiple height-increasing rare and low-frequency nonsynonymous variants (SLC27A3 and CYP26B1; PSKAT-O < 2.5 × 10−6). Our analysis shows a general tendency of the effect sizes of rare variants towards increasing height, which is contrary to findings among Europeans, suggesting that height-associated rare variants are under different selection pressure in Japanese and European populations.

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Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus)

Scientific Reports ◽

10.1038/s41598-020-76166-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Georgina Samaha ◽

Claire M. Wade ◽

Julia Beatty ◽

Leslie A. Lyons ◽

Linda M. Fleeman ◽

...

Keyword(s):

Diabetes Mellitus ◽

Genome Wide Association Study ◽

Genetic Model ◽

Sequence Data ◽

Pancreatic Beta Cell ◽

Whole Genome Sequence ◽

Cell Dysfunction ◽

Genome Wide ◽

A Genome ◽

Pathologic Features

Abstract Diabetes mellitus, a common endocrinopathy affecting domestic cats, shares many clinical and pathologic features with type 2 diabetes in humans. In Australia and Europe, diabetes mellitus is almost four times more common among Burmese cats than in other breeds. As a genetically isolated population, the diabetic Australian Burmese cat provides a spontaneous genetic model for studying diabetes mellitus in humans. Studying complex diseases in pedigreed breeds facilitates tighter control of confounding factors including population stratification, allelic frequencies and environmental heterogeneity. We used the feline SNV array and whole genome sequence data to undertake a genome wide-association study and runs of homozygosity analysis, of a case–control cohort of Australian and European Burmese cats. Our results identified diabetes-associated haplotypes across chromosomes A3, B1 and E1 and selective sweeps across the Burmese breed on chromosomes B1, B3, D1 and D4. The locus on chromosome B1, common to both analyses, revealed coding and splice region variants in candidate genes, ANK1, EPHX2 and LOX2, implicated in diabetes mellitus and lipid dysregulation. Mapping this condition in Burmese cats has revealed a polygenic spectrum, implicating loci linked to pancreatic beta cell dysfunction, lipid dysregulation and insulin resistance in the pathogenesis of diabetes mellitus in the Burmese cat.

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Pigment Intensity in Dogs is Associated with a Copy Number Variant Upstream of KITLG

Genes ◽

10.3390/genes11010075 ◽

2020 ◽

Vol 11 (1) ◽

pp. 75 ◽

Cited By ~ 5

Author(s):

Kalie Weich ◽

Verena Affolter ◽

Daniel York ◽

Robert Rebhun ◽

Robert Grahn ◽

...

Keyword(s):

Copy Number ◽

Genome Wide Association Study ◽

Coat Color ◽

Sequence Data ◽

Copy Number Variant ◽

Color Variation ◽

Domestic Dog ◽

Whole Genome Sequence ◽

Hair Color ◽

A Genome

Dogs exhibit a wide variety of coat color types, and many genes have been identified that control pigment production, appearance, and distribution. Some breeds, such as the Nova Scotia Duck Tolling Retriever (NSDTR), exhibit variation in pheomelanin pigment intensity that is not explained by known genetic variants. A genome-wide association study comparing light red to dark red in the NSDTR identified a significantly associated region on canine chromosome 15 (CFA 15:23 Mb–38 Mb). Coverage analysis of whole genome sequence data from eight dogs identified a 6 kb copy number variant (CNV) 152 kb upstream of KITLG. Genotyping with digital droplet PCR (ddPCR) confirmed a significant association between an increased copy number with the dark-red coat color in NSDTR (p = 6.1 × 10−7). The copy number of the CNV was also significantly associated with coat color variation in both eumelanin and pheomelanin-based Poodles (p = 1.5 × 10−8, 4.0 × 10−9) and across other breeds. Moreover, the copy number correlated with pigment intensity along the hair shaft in both pheomelanin and eumelanin coats. KITLG plays an important role in melanogenesis, and variants upstream of KITLG have been associated with coat color variation in mice as well as hair color in humans consistent with its role in the domestic dog.

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Whole-genome sequence-based analysis of thyroid function

Nature Communications ◽

10.1038/ncomms6681 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 44

Author(s):

Peter N. Taylor ◽

◽

Eleonora Porcu ◽

Shelby Chew ◽

Purdey J. Campbell ◽

...

Keyword(s):

Thyroid Function ◽

Genome Sequence ◽

Rare Variants ◽

Sequence Data ◽

Association Studies ◽

Meta Analysis ◽

Low Frequency ◽

Whole Genome Sequence ◽

Whole Genome ◽

Common Variants

Abstract Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10−9) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10−14). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10−9) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10−11). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

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Identification of loci associated with pathological outcomes in Holstein cattle infected with Mycobacterium avium subsp. paratuberculosis using whole-genome sequence data

Scientific Reports ◽

10.1038/s41598-021-99672-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Maria Canive ◽

Gerard Badia-Bringué ◽

Patricia Vázquez ◽

Oscar González-Recio ◽

Almudena Fernández ◽

...

Keyword(s):

Candidate Genes ◽

Mycobacterium Avium ◽

Genome Wide Association Study ◽

Cholesterol Metabolism ◽

Sequence Data ◽

Plasma Cholesterol ◽

Whole Genome Sequence ◽

Whole Genome ◽

Histological Lesion ◽

A Genome

AbstractBovine paratuberculosis (PTB), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis that affects cattle worldwide. According to their severity and extension, PTB-associated histological lesions have been classified into the following groups; focal, multifocal, and diffuse. It is unknown whether these lesions represent sequential stages or divergent outcomes. In the current study, the associations between host genetic and pathology were explored by genotyping 813 Spanish Holstein cows with no visible lesions (N = 373) and with focal (N = 371), multifocal (N = 33), and diffuse (N = 33) lesions in gut tissues and regional lymph nodes. DNA from peripheral blood samples of these animals was genotyped with the bovine EuroG MD Bead Chip, and the corresponding genotypes were imputed to whole-genome sequencing (WGS) data using the 1000 Bull genomes reference population. A genome-wide association study (GWAS) was performed using the WGS data and the presence or absence of each type of histological lesion in a case–control approach. A total of 192 and 92 single nucleotide polymorphisms (SNPs) defining 13 and 9 distinct quantitative trait loci (QTLs) were highly-associated (P ≤ 5 × 10−7) with the multifocal (heritability = 0.075) and the diffuse (heritability = 0.189) lesions, respectively. No overlap was seen in the SNPs controlling these distinct pathological outcomes. The identified QTLs overlapped with some QTLs previously associated with PTB susceptibility, bovine tuberculosis susceptibility, clinical mastitis, somatic cell score, bovine respiratory disease susceptibility, tick resistance, IgG level, and length of productive life. Pathway analysis with candidate genes overlapping the identified QTLs revealed a significant enrichment of the keratinization pathway and cholesterol metabolism in the animals with multifocal and diffuse lesions, respectively. To test whether the enrichment of SNP variants in candidate genes involved in the cholesterol metabolism was associated with the diffuse lesions; the levels of total cholesterol were measured in plasma samples of cattle with focal, multifocal, or diffuse lesions or with no visible lesions. Our results showed reduced levels of plasma cholesterol in cattle with diffuse lesions. Taken together, our findings suggested that the variation in MAP-associated pathological outcomes might be, in part, genetically determined and indicative of distinct host responses.

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Genome-wide identification of lineage and locus specific variation associated with pneumococcal carriage duration

10.1101/107086 ◽

2017 ◽

Cited By ~ 1

Author(s):

John A. Lees ◽

Nicholas J. Croucher ◽

Goldblatt David ◽

Nosten Francois ◽

Parkhill Julian ◽

...

Keyword(s):

Environmental Factors ◽

Low Income ◽

Genome Wide Association Study ◽

Sequence Data ◽

Genomic Variation ◽

Whole Genome Sequence ◽

Vaccine Response ◽

Pneumococcal Carriage ◽

Genome Wide ◽

A Genome

AbstractStreptococcus pneumoniae is a leading cause of invasive disease in infants, especially in low-income settings. Asymptomatic carriage in the nasopharynx is a prerequisite for disease, and the duration of carriage is an important consideration in modelling transmission dynamics and vaccine response. Existing studies of carriage duration variability are based at the serotype level only, and do not probe variation within lineages or fully quantify interactions with other environmental factors.Here we developed a model to calculate the duration of carriage episodes from longitudinal swab data. By combining these results with whole genome sequence data we estimate that pneumococcal genomic variation accounted for 63% of the phenotype variation, whereas host traits accounted for less than 5%. We further partitioned this heritability into both lineage and locus effects, and quantified the amount attributable to the largest sources of variation in carriage duration: serotype (17%), drug-resistance (9%) and other significant locus effects (7%). For the locus effects, a genome-wide association study identified 16 loci which may have an effect on carriage duration independent of serotype. Hits at a genome-wide level of significance were to prophage sequences, suggesting infection by such viruses substantially affects carriage duration.These results show that both serotype and non-serotype specific effects alter carriage duration in infants and young children and are more important than other environmental factors such as host genetics. This has implications for models of pneumococcal competition and antibiotic resistance, and leads the way for the analysis of heritability of complex bacterial traits.Significance statementOther than serotype, the genetic determinants of pneumococcal carriage duration are unknown. In this study we used longitudinal sampling to measure the duration of carriage in infants, and searched for any associated variation in the pan-genome. While we found that the pathogen genome explains most of the variability in duration, serotype did not fully account for this. Recent theoretical work has proposed the existence of alleles which alter carriage duration to explain the puzzle of continued coexistence of antibiotic-resistant and sensitive strains. Here we have shown that these alleles do exist in a natural population, and also identified candidates for the loci which fulfil this role. Together these findings have implications for future modelling of pneumococcal epidemiology and resistance.

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Imputation accuracy to whole-genome sequence in Nellore cattle

Genetics Selection Evolution ◽

10.1186/s12711-021-00622-5 ◽

2021 ◽

Vol 53 (1) ◽

Author(s):

Gerardo A. Fernandes Júnior ◽

Roberto Carvalheiro ◽

Henrique N. de Oliveira ◽

Mehdi Sargolzaei ◽

Roy Costilla ◽

...

Keyword(s):

Beef Cattle ◽

Genome Sequence ◽

Rare Variants ◽

Imputation Accuracy ◽

Low Frequency ◽

Cost Effective ◽

Target Population ◽

Genotype Imputation ◽

Whole Genome Sequence ◽

Whole Genome

Abstract Background A cost-effective strategy to explore the complete DNA sequence in animals for genetic evaluation purposes is to sequence key ancestors of a population, followed by imputation mechanisms to infer marker genotypes that were not originally reported in a target population of animals genotyped with single nucleotide polymorphism (SNP) panels. The feasibility of this process relies on the accuracy of the genotype imputation in that population, particularly for potential causal mutations which may be at low frequency and either within genes or regulatory regions. The objective of the present study was to investigate the imputation accuracy to the sequence level in a Nellore beef cattle population, including that for variants in annotation classes which are more likely to be functional. Methods Information of 151 key sequenced Nellore sires were used to assess the imputation accuracy from bovine HD BeadChip SNP (~ 777 k) to whole-genome sequence. The choice of the sires aimed at optimizing the imputation accuracy of a genotypic database, comprised of about 10,000 genotyped Nellore animals. Genotype imputation was performed using two computational approaches: FImpute3 and Minimac4 (after using Eagle for phasing). The accuracy of the imputation was evaluated using a fivefold cross-validation scheme and measured by the squared correlation between observed and imputed genotypes, calculated by individual and by SNP. SNPs were classified into a range of annotations, and the accuracy of imputation within each annotation classification was also evaluated. Results High average imputation accuracies per animal were achieved using both FImpute3 (0.94) and Minimac4 (0.95). On average, common variants (minor allele frequency (MAF) > 0.03) were more accurately imputed by Minimac4 and low-frequency variants (MAF ≤ 0.03) were more accurately imputed by FImpute3. The inherent Minimac4 Rsq imputation quality statistic appears to be a good indicator of the empirical Minimac4 imputation accuracy. Both software provided high average SNP-wise imputation accuracy for all classes of biological annotations. Conclusions Our results indicate that imputation to whole-genome sequence is feasible in Nellore beef cattle since high imputation accuracies per individual are expected. SNP-wise imputation accuracy is software-dependent, especially for rare variants. The accuracy of imputation appears to be relatively independent of annotation classification.

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

Nature ◽

10.1038/s41586-021-03205-y ◽

2021 ◽

Vol 590 (7845) ◽

pp. 290-299 ◽

Cited By ~ 22

Author(s):

Daniel Taliun ◽

◽

Daniel N. Harris ◽

Michael D. Kessler ◽

Jedidiah Carlson ◽

...

Keyword(s):

Rare Variants ◽

Sequence Data ◽

Association Studies ◽

Genotype Imputation ◽

Genome Wide Association Studies ◽

Phenotypic Data ◽

Treatment And Prevention ◽

Genome Wide ◽

Diverse Backgrounds ◽

Unmapped Reads

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

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Identification and fine-mapping of a major QTL (qRtsc8-1) conferring resistance to maize tar spot complex and production markers validation in breeding lines

10.21203/rs.3.rs-1072295/v1 ◽

2021 ◽

Author(s):

Jiaojiao Ren ◽

Penghao Wu ◽

Gordon M. Huestis ◽

Ao Zhang ◽

Jingtao Qu ◽

...

Keyword(s):

Latin American ◽

Fine Mapping ◽

Genome Wide Association Study ◽

Selective Genotyping ◽

Doubled Haploid Population ◽

Phenotypic Variance ◽

Breeding Lines ◽

A Genome ◽

Tar Spot ◽

Major Qtl

Abstract Tar spot complex (TSC) is a major foliar disease of maize in many Central and Latin American countries and leads to severe yield loss. To dissect the genetic architecture of TSC resistance, a genome-wide association study (GWAS) panel and a bi-parental doubled haploid population were used for GWAS and selective genotyping analysis, respectively. A total of 115 SNPs in bin 8.03 were detected by GWAS and three QTL in bins 6.05, 6.07, and 8.03 were detected by selective genotyping. The major QTL qRtsc8-1 located in bin 8.03 was detected by both analyses, it explained 14.97% of the phenotypic variance. To fine-map qRtsc8-1, the recombinant-derived progeny test was implemented. Recombinations in each generation were backcrossed, and the backcross progenies were genotyped with Kompetitive Allele Specific PCR (KASP) markers and phenotyped for TSC resistance individually. The significant tests for comparing the TSC resistance between the two classes of progenies with and without resistant alleles were used for fine-mapping. In BC5 generation, qRtsc8-1 was fine mapped in an interval of ~721 kb flanked by markers of KASP81160138 and KASP81881276. In this interval, the candidate genes GRMZM2G063511 and GRMZM2G073884 were identified, which encode an integral membrane protein-like and a leucine-rich repeat receptor-like protein kinase, respectively. Both genes are involved in maize disease resistance responses. Two production markers KASP81160138 and KASP81160155 were verified in 471 breeding lines. This study provides valuable information for cloning the resistance gene, it will also facilitate the routine implementation of marker-assisted selection in the breeding pipeline for improving TSC resistance.

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Identification of misclassified ClinVar variants using disease population prevalence

10.1101/075416 ◽

2016 ◽

Cited By ~ 4

Author(s):

Naisha Shah ◽

Ying-Chen Claire Hou ◽

Hung-Chun Yu ◽

Rachana Sainger ◽

Eric Dec ◽

...

Keyword(s):

Genetic Risk ◽

Rare Variants ◽

Sequence Data ◽

Critical Role ◽

Significant Proportion ◽

Whole Genome Sequence ◽

Supporting Evidence ◽

Level Of Evidence ◽

Population Prevalence

ABSTRACTThere is a significant interest in the standardized classification of human genetic variants. The availability of new large datasets generated through genome sequencing initiatives provides a ground for the computational evaluation of the supporting evidence. We used whole genome sequence data from 8,102 unrelated individuals to analyze the adequacy of estimated rates of disease on the basis of genetic risk and the expected population prevalence of the disease. Analyses included the ACMG recommended 56 gene-condition sets for incidental findings and 631 genes associated with 348 OrphaNet conditions. A total of 21,004 variants were used to identify patterns of inflation (i.e. excess genetic risk). Inflation, i.e., misclassification, increases as the level of evidence in ClinVar supporting the pathogenic nature of the variant decreases. The burden of rare variants was a main contributing factor of the observed inflation indicating misclassified benign private mutations. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time. The study strongly suggests that ClinVar includes a significant proportion of wrongly ascertained variants, and underscores the critical role of ClinVar to contrast claims, and foster validation across submitters.

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Monogenic and Polygenic Contributions to QTc Prolongation in the Population

10.1101/2021.06.18.21258578 ◽

2021 ◽

Author(s):

Victor Nauffal ◽

Valerie N Morrill ◽

Sean J Jurgens ◽

Seung Hoan Choi ◽

Amelia W Hall ◽

...

Keyword(s):

Qt Interval ◽

Genome Wide Association Study ◽

Rare Variants ◽

Phenotypic Expression ◽

Polygenic Risk Score ◽

Interval Duration ◽

Polygenic Risk ◽

A Genome ◽

Qt Interval Duration ◽

Polygenic Variation

Background: Rare sequence variation in genes underlying the long QT syndrome (LQTS) and common polygenic variation influence QT interval duration. It is unclear how rare and common variation contribute to QT interval duration in the general population. Objectives: Investigate monogenic and polygenic contributions to QT interval duration and the role of polygenic variation in modulating phenotypic expression of rare monogenic variation. Methods: We performed a genome wide association study (GWAS) of QTc duration in 44,979 United Kingdom Biobank (UKBB) participants and created a polygenic risk score (PRS). The PRS was validated in 39,800 independent UKBB participants. Among 26,976 participants with whole genome sequencing and ECG data in the TransOmics for Precision Medicine (TOPMed) program, we identified 160 carriers of putative pathogenic rare variants in 10 LQTS genes. We examined QTc associations with the PRS and with LQTS rare variants in TOPMed. Results: Twenty independent loci (4 novel) were identified by GWAS. The PRS comprising 565 common variants was significantly associated with QTc duration in TOPMed (p=1.1x10-64). Carriers of LQTS rare variants had longer QTc intervals than non-carriers (deltaQTc=10.9 ms [7.4-14.4] for all LQTS genes; deltaQTc=26.5 ms [20.7-32.3] for KCNQ1, KCNH2 and SCN5A). 16.7% of individuals with QTc>480 ms carried either a rare variant in a LQTS gene or had a PRS in the top decile (3.4% monogenic, 13.6% top decile of PRS). We observed a greater effect of rare variants on the QTc among individuals with a higher polygenic risk (lowest PRS tertile:deltaQTccarrier/non-carrier=4.8 ms [-1.2-10.7];highest PRS tertile:deltaQTccarrier/non-carrier=18.9 ms [12.8-25.1];p-interaction=0.001). Conclusions: QTc duration is influenced by both rare variants in established LQTS genes and polygenic risk. The phenotypic expression of monogenic variation is modulated by polygenic variation. Nevertheless, over 80% of individuals with prolonged QTc do not carry a rare monogenic variant or polygenic risk equivalent.

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