scholarly journals An exploration of linkage fine-mapping on sequences from case-control studies

2021 ◽  
Author(s):  
Payman Nickchi ◽  
Charith B Karunarathna ◽  
Jinko Graham
Keyword(s):  
Linkage Analysis ◽  
Sequence Data ◽  
Population Sample ◽  
Population Based ◽  
Case Control Studies ◽  
Linkage Methods ◽  
Causal Variants ◽  
Genotypic Association ◽  
Sequence Relatedness ◽  
Genomic Regions

Linkage analysis maps genetic loci for a heritable trait by identifying genomic regions with excess relatedness among individuals with similar trait values. Analysis may be conducted on related individuals from families, or on samples of unrelated individuals from a population. For allelically heterogeneous traits, population-based linkage analysis can be more powerful than genotypic-association analysis. Here, we focus on linkage analysis in a population sample, but use sequences rather than individuals as our unit of observation. Earlier investigations of sequence-based linkage mapping relied on known sequence relatedness, whereas we infer relatedness from the sequence data. We propose two ways to associate similarity in relatedness of sequences with similarity in their trait values and compare the resulting linkage methods to two genotypic- association methods. We also introduce a procedure to label case sequences as potential carriers or non-carriers of causal variants after an association has been found. This post-hoc labeling of case sequences is based on inferred relatedness to other case sequences. Our simulation results indicate that methods based on sequence-relatedness improve localization and perform as well as genotypic-association methods for detecting rare causal variants. Sequence-based linkage analysis therefore has potential to fine-map allelically heterogeneous disease traits.

scholarly journals Allergic diseases attributable to atopy in a population sample of Asian children

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chao-Yi Wu ◽  
Hsin-Yi Huang ◽  
Wen-Chi Pan ◽  
Sui-Ling Liao ◽  
Man-Chin Hua ◽  
...  
Keyword(s):  
Immunoglobulin E ◽  
Population Attributable Risk ◽  
Population Sample ◽  
International Study ◽  
Allergic Diseases ◽  
Population Based ◽  
School Age Children ◽  
Specific Immunoglobulin E ◽  
Asian Children ◽  
Specific Immunoglobulin

AbstractThe proportion of allergic diseases attributable to atopy remains a subject of controversy. This study aimed to estimate the population risk of physician-diagnosed asthma, rhinitis and eczema attributed to atopy among a population sample of Asian school-age children. Asian children aged 5–18 years (n = 1321) in the Prediction of Allergies in Taiwanese CHildren (PATCH) study were tested for serum allergen-specific immunoglobulin E. Physician-diagnosed asthma, rhinitis and eczema were assessed by a modified International Study of Asthma and Allergies in Childhood questionnaire. Atopy was defined as the presence of serum allergen-specific immunoglobulin E. In this population-based study, 50.4% of the subjects with asthma, 46.3% with rhinitis, and 46.7% with eczema were attributable to atopy. The population attributable risk (PAR) of atopy for three allergic diseases was higher in adolescents (asthma, 54.4%; rhinitis, 59.6%; eczema, 49.5%) than younger children aged less than 10 years (asthma, 46.9%; rhinitis, 39.5%; eczema, 41.9%). Among the seven allergen categories, sensitization to mites had the highest PARs for all three allergic diseases (51.3 to 64.1%), followed by sensitization to foods (asthma, 7.1%; rhinitis, 10.4%; eczema 27.7%). In conclusion, approximately half (46.3 to 50.4%) of Asian children in Taiwan with allergic diseases are attributable to atopy.

scholarly journals A machine learning case–control classifier for schizophrenia based on DNA methylation in blood

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chathura J. Gunasekara ◽  
Eilis Hannon ◽  
Harry MacKay ◽  
Cristian Coarfa ◽  
Andrew McQuillin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Population Based ◽  
Case Control ◽  
Training Data ◽  
Polygenic Risk Score ◽  
Reverse Causality ◽  
Cell Type Specificity ◽  
Data Set ◽  
Human Genomic ◽  
Genomic Regions

AbstractEpigenetic dysregulation is thought to contribute to the etiology of schizophrenia (SZ), but the cell type-specificity of DNA methylation makes population-based epigenetic studies of SZ challenging. To train an SZ case–control classifier based on DNA methylation in blood, therefore, we focused on human genomic regions of systemic interindividual epigenetic variation (CoRSIVs), a subset of which are represented on the Illumina Human Methylation 450K (HM450) array. HM450 DNA methylation data on whole blood of 414 SZ cases and 433 non-psychiatric controls were used as training data for a classification algorithm with built-in feature selection, sparse partial least squares discriminate analysis (SPLS-DA); application of SPLS-DA to HM450 data has not been previously reported. Using the first two SPLS-DA dimensions we calculated a “risk distance” to identify individuals with the highest probability of SZ. The model was then evaluated on an independent HM450 data set on 353 SZ cases and 322 non-psychiatric controls. Our CoRSIV-based model classified 303 individuals as cases with a positive predictive value (PPV) of 80%, far surpassing the performance of a model based on polygenic risk score (PRS). Importantly, risk distance (based on CoRSIV methylation) was not associated with medication use, arguing against reverse causality. Risk distance and PRS were positively correlated (Pearson r = 0.28, P = 1.28 × 10−12), and mediational analysis suggested that genetic effects on SZ are partially mediated by altered methylation at CoRSIVs. Our results indicate two innate dimensions of SZ risk: one based on genetic, and the other on systemic epigenetic variants.

scholarly journals Symposium report: breast cancer in India—trends, environmental exposures and clinical implications

2021 ◽  
Vol 32 (6) ◽  
pp. 567-575
Author(s):  
Jasmine A. McDonald ◽  
Roshni Rao ◽  
Marley Gibbons ◽  
Rajiv Janardhanan ◽  
Surinder Jaswal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Scientific Evidence ◽  
Treatment Options ◽  
Environmental Exposures ◽  
Population Based ◽  
Clinical Implications ◽  
Think Tank ◽  
Case Control Studies ◽  
Short Term

Abstract Purpose Incidence of breast cancer (BC), particularly in young women, are rising in India. Without population-based mammography screening, rising rates cannot be attributed to screening. Investigations are needed to understand the potential drivers of this trend. Methods An international team of experts convened to discuss the trends, environmental exposures, and clinical implications associated with BC in India and outlined recommendations for its management. Results Panels were structured across three major BC themes (n = 10 presentations). The symposium concluded with a semi-structured Think Tank designed to elicit short-term and long-term goals that could address the challenges of BC in India. Conclusion There was consensus that the prevalence of late-stage BC and the high BC mortality rates are associated with the practice of detection, which is primarily through clinical and self-breast exams, as opposed to mammography. Triple-Negative BC (TNBC) was extensively discussed, including TNBC etiology and potential risk factors, the limited treatment options, and if reported TNBC rates are supported by rigorous scientific evidence. The Think Tank session yielded long-term and short-term goals to further BC reduction in India and included more regional etiological studies on environmental exposures using existing India-based cohorts and case–control studies, standardization for molecular subtyping of BC cases, and improving the public’s awareness of breast health.

scholarly journals Modeling Linkage Disequilibrium and Identifying Recombination Hotspots Using Single-Nucleotide Polymorphism Data

Genetics ◽  
2003 ◽  
Vol 165 (4) ◽  
pp. 2213-2233 ◽  
Author(s):  
Na Li ◽  
Matthew Stephens
Keyword(s):  
Linkage Disequilibrium ◽  
Recombination Rate ◽  
Population Sample ◽  
Simulated Data ◽  
Region Of Interest ◽  
Population Data ◽  
Recombination Rates ◽  
Single Nucleotide ◽  
Recombination Hotspots ◽  
Genomic Regions

AbstractWe introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process; (ii) considering all loci simultaneously, rather than pairwise; (iii) avoiding the assumption that LD necessarily has a “block-like” structure; and (iv) being computationally tractable for huge genomic regions (up to complete chromosomes). We examine in detail one natural application of the model: estimation of underlying recombination rates from population data. Using simulation, we show that in the case where recombination is assumed constant across the region of interest, recombination rate estimates based on our model are competitive with the very best of current available methods. More importantly, we demonstrate, on real and simulated data, the potential of the model to help identify and quantify fine-scale variation in recombination rate from population data. We also outline how the model could be useful in other contexts, such as in the development of more efficient haplotype-based methods for LD mapping.

scholarly journals Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1378
Author(s):  
Tú Nguyen-Dumont ◽  
James G. Dowty ◽  
Jason A. Steen ◽  
Anne-Laure Renault ◽  
Fleur Hammet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cumulative Risk ◽  
Population Based ◽  
Case Control ◽  
Cancer Information ◽  
Case Control Studies ◽  
Breast Cancer Family ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Control Family

Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

46 Footprints of Selection in Angus and Hanwoo Beef Cattle Using Imputed Whole Genome Sequence Data

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 25-25
Author(s):  
Muhammad Yasir Nawaz ◽  
Rodrigo Pelicioni Savegnago ◽  
Cedric Gondro
Keyword(s):  
Beef Cattle ◽  
Genome Sequence ◽  
Sequence Data ◽  
Whole Genome Sequence ◽  
Fixation Index ◽  
Whole Genome ◽  
Extended Haplotype Homozygosity ◽  
Extended Haplotype ◽  
Genome Sequence Data ◽  
Genomic Regions

Abstract In this study, we detected genome wide footprints of selection in Hanwoo and Angus beef cattle using different allele frequency and haplotype-based methods based on imputed whole genome sequence data. Our dataset included 13,202 Angus and 10,437 Hanwoo animals with 10,057,633 and 13,241,550 imputed SNPs, respectively. A subset of data with 6,873,624 common SNPs between the two populations was used to estimate signatures of selection parameters, both within (runs of homozygosity and extended haplotype homozygosity) and between (allele fixation index, extended haplotype homozygosity) the breeds in order to infer evidence of selection. We observed that correlations between various measures of selection ranged between 0.01 to 0.42. Assuming these parameters were complementary to each other, we combined them into a composite selection signal to identify regions under selection in both beef breeds. The composite signal was based on the average of fractional ranks of individual selection measures for every SNP. We identified some selection signatures that were common between the breeds while others were independent. We also observed that more genomic regions were selected in Angus as compared to Hanwoo. Candidate genes within significant genomic regions may help explain mechanisms of adaptation, domestication history and loci for important traits in Angus and Hanwoo cattle. In the future, we will use the top SNPs under selection for genomic prediction of carcass traits in both breeds.

Abstract P249: Incident Sleep-Disordered Breathing is Associated with Obesity: Penn State Child Cohort

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Edward O Bixler ◽  
Alexandros N Vgontzas ◽  
Duanping Liao ◽  
Susan Calhoun ◽  
Julio Fernandez-Mendoza ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Sleep Disordered Breathing ◽  
Population Sample ◽  
Population Based ◽  
Penn State ◽  
Potential Risk Factors ◽  
State Child ◽  
Disordered Breathing

Objectives: To study the epidemiology of sleep-disordered breathing (SDB) in adolescents, which has received little attention. Methods: The Penn State Child Cohort (PSCC) is a representative general population sample of 700 children aged 5-12 years. Our preliminary results are based on an average 8 year follow up of the initial 300 prospective subjects (~43%) from this ongoing cohort study. A logistic regression was used to assess the association between potential risk factors and incident SDB. Results: The mean age at the 8-year follow up examination was 17.2 ± 0.1 years, with an average BMI percentile of 66.6 ± 1.6 and 56.5% boys. At baseline 1.5% of this subsample had SDB, defined by Apnea Hypopnia Index (AHI > 5 /hour). Surprisingly, there was no persistence of SDB. Eight-year incident SDB was 10.5%. The average AHI in those with incident SDB was 12.7 with a maximum of 92.4. Incident SDB was similar for girls (7.8%) and boys (12.7%). Those with SDB were older than those without (18.7 vs 17.0 years, P<0.001) and girls with SDB were older than boys with SDB (20.0 vs 18.0 years, P=0.002). Those with incident SDB tended to have a greater change in BMI percentile (8.2 vs 1.8, P = 0.143) during the follow up and slightly higher minority representation (25.8% vs 21.9%, P=0.655). A logistic regression model identified three variables that were associated with incident SDB, controlling for baseline AHI: age (OR = 1.5 (1.3, 1.9) P<0.001), male (OR= 2.5 (1.11,10.00) P=0.021), and [[Unable to Display Character: &#8710;]]BMIPCT (OR=1.2(1.02, 1.5) P=0.032). Conclusion: In this population based sample of adolescents, the 8-year incidence of SDB was high (10.5%), whereas childhood SDB did not persist into adolescence. Further, the results indicate that risk factors for incident SDB in adolescents are age, male and the development of obesity.

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