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BioRxiv : the Preprint Server For... May 2024Runs of homozygosity (ROH) are genomic regions that arise when two copies of an identical ancestral haplotype are inherited from parents with a recent common ancestor....
Runs of homozygosity (ROH) are genomic regions that arise when two copies of an identical ancestral haplotype are inherited from parents with a recent common ancestor. In this study, we performed a novel comprehensive analysis to infer genetic diversity among dogs and quantified the association between ROH and non-disease phenotypes. We found distinct patterns of genetic diversity across clades of breed dogs and elevated levels of long ROH, compared to non- domesticated dogs. These high levels of F (inbreeding coefficient) are a consequence of recent inbreeding among domesticated dogs during breed establishment. We identified statistically significant associations between F and height, weight, lifespan, muscled, white head, white chest, furnish, and length of fur. After correcting for population structure, we identified more than 45 genes across the three examined quantitative traits that exceeded the threshold for suggestive significance, indicating significant polygenic inheritance for the complex quantitative phenotypes in dogs.
PubMed: 38746159
DOI: 10.1101/2024.05.01.592072 -
Psychiatry Research Jul 2024What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and...
What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRS associations were linked to multiple phenotypes, PheRS showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.
Topics: Humans; Stress Disorders, Post-Traumatic; Resilience, Psychological; Electronic Health Records; Female; Male; Middle Aged; Adult; Aged; Genetic Predisposition to Disease; Phenotype; Sleep Wake Disorders; Comorbidity; Multifactorial Inheritance; United Kingdom; Genome-Wide Association Study
PubMed: 38744179
DOI: 10.1016/j.psychres.2024.115950 -
JAMA Network Open May 2024Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height...
IMPORTANCE
Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height or cognitive ability) in human embryos, with the goal of selecting which embryos to use. Given its commercial availability and concerns raised by researchers, clinicians, bioethicists, and professional organizations, it is essential to inform key stakeholders and relevant policymakers about the public's perspectives on this technology.
OBJECTIVE
To survey US adults to examine general attitudes, interests, and concerns regarding PES use.
DESIGN, SETTING, AND PARTICIPANTS
For this survey study, data were collected from 1 stratified sample and 1 nonprobability sample (samples 1 and 2, respectively) between March and July 2023. The surveys measured approval, interest, and concerns regarding various applications of PES. In the second sample, presentation of a list of potential concerns was randomized (presented at survey onset vs survey end). The survey was designed using Qualtrics and distributed to participants through Prolific, an online sampling firm. Sample 1 was nationally representative with respect to gender, age, and race and ethnicity; sample 2 was recruited without specific demographic criteria. Analyses were conducted between March 2023 and February 2024.
MAIN OUTCOMES AND MEASURES
Participants reported their approval, interest, and concerns regarding various applications of PES and outcomes screened (eg, traits and conditions). Statistical analysis was conducted using independent samples t tests and repeated-measures analyses of variance.
RESULTS
Of the 1435 respondents in sample 1, demographic data were available for 1427 (mean [SD] age, 45.8 [16.0] years; 724 women [50.7%]). Among these 1427 sample 1 respondents, 1027 (72.0%) expressed approval for PES and 1169 (81.9%) expressed some interest in using PES if already undergoing in vitro fertilization (IVF). Approval among these respondents for using PES for embryo selection was notably high for physical health conditions (1109 [77.7%]) and psychiatric health conditions (1028 [72.0%]). In contrast, there was minority approval for embryo selection based on PES for behavioral traits (514 [36.0%]) and physical traits (432 [30.3%]). Nevertheless, concerns about PES leading to false expectations and promoting eugenic practices were pronounced, with 787 of 1422 (55.3%) and 780 of 1423 (54.8%) respondents finding them very to extremely concerning, respectively. Sample 2 included 192 respondents (mean [SD] age 37.7 [12.2] years; 110 men [57.3%]). These respondents were presented concerns at survey onset (n = 95) vs survey end (n = 97), which was associated with less approval (28-percentage point decrease) and more uncertainty (24 percentage-point increase) but with only slightly higher disapproval (4 percentage-point increase).
CONCLUSIONS AND RELEVANCE
These findings suggest that it is critical for health care professionals and medical societies to consider and understand the perspectives of diverse stakeholders (eg, patients undergoing IVF, clinicians, and the general public), given the absence of regulation and the recent commercial availability of PES.
Topics: Humans; Female; Adult; Male; Public Opinion; Middle Aged; Surveys and Questionnaires; United States; Multifactorial Inheritance; Genetic Testing
PubMed: 38743425
DOI: 10.1001/jamanetworkopen.2024.10832 -
PloS One 2024The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene,...
The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene, polygenic traits are influenced by multiple genetic loci, each exerting a modest effect on the trait. This cumulative impact of numerous genes, interactions among them, environmental factors, and epigenetic modifications results in a multifaceted architecture of genetic contributions to complex traits. Given the well-characterized genome, diverse traits, and range of genetic resources, chicken (Gallus gallus) was employed as a model organism to dissect the intricate genetic makeup of a previously identified major Quantitative Trait Loci (QTL) for body weight on chromosome 1. A multigenerational advanced intercross line (AIL) of 3215 chickens whose genomes had been sequenced to an average of 0.4x was analyzed using genome-wide association study (GWAS) and variance-heterogeneity GWAS (vGWAS) to identify markers associated with 8-week body weight. Additionally, epistatic interactions were studied using the natural and orthogonal interaction (NOIA) model. Six genetic modules, two from GWAS and four from vGWAS, were strongly associated with the studied trait. We found evidence of both additive- and non-additive interactions between these modules and constructed a putative local epistasis network for the region. Our screens for functional alleles revealed a missense variant in the gene ribonuclease H2 subunit B (RNASEH2B), which has previously been associated with growth-related traits in chickens and Darwin's finches. In addition, one of the most strongly associated SNPs identified is located in a non-coding region upstream of the long non-coding RNA, ENSGALG00000053256, previously suggested as a candidate gene for regulating chicken body weight. By studying large numbers of individuals from a family material using approaches to capture both additive and non-additive effects, this study advances our understanding of genetic complexities in a highly polygenic trait and has practical implications for poultry breeding and agriculture.
Topics: Animals; Chickens; Quantitative Trait Loci; Genome-Wide Association Study; Body Weight; Polymorphism, Single Nucleotide; Epistasis, Genetic; Phenotype; Female; Multifactorial Inheritance; Male
PubMed: 38739572
DOI: 10.1371/journal.pone.0295109 -
International Journal of Molecular... Apr 2024Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying... (Review)
Review
Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.
Topics: Humans; Mitochondrial Diseases; Rare Diseases; Genetic Predisposition to Disease; Epigenesis, Genetic; Multifactorial Inheritance; Animals
PubMed: 38731822
DOI: 10.3390/ijms25094602 -
A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.Hepatology Communications Jun 2024Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We...
BACKGROUND
Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis.
METHODS
Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239).
RESULTS
A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis.
CONCLUSIONS
PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.
Topics: Humans; Polymorphism, Single Nucleotide; Liver Cirrhosis, Alcoholic; Male; Female; Middle Aged; Genome-Wide Association Study; White People; Multifactorial Inheritance; Aged; Risk Assessment; Alcohol Drinking; Adult; Risk Factors; Genetic Predisposition to Disease; United Kingdom; Genetic Risk Score
PubMed: 38727677
DOI: 10.1097/HC9.0000000000000431 -
Multiple polygenic risk scores can improve the prediction of systemic lupus erythematosus in Taiwan.Lupus Science & Medicine May 2024To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE.
OBJECTIVE
To identify new genetic variants associated with SLE in Taiwan and establish polygenic risk score (PRS) models to improve the early diagnostic accuracy of SLE.
METHODS
The study enrolled 2429 patients with SLE and 48 580 controls from China Medical University Hospital in Taiwan. A genome-wide association study (GWAS) and PRS analyses of SLE and other three SLE markers, namely ANA, anti-double-stranded DNA antibody (dsDNA) and anti-Smith antibody (Sm), were conducted.
RESULTS
Genetic variants associated with SLE were identified through GWAS. Some novel genes, which have been previously reported, such as and , were revealed to be associated with SLE in Taiwan. Multiple PRS models were established, and optimal cut-off points for each PRS were determined using the Youden Index. Combining the PRSs for SLE, ANA, dsDNA and Sm yielded an area under the curve of 0.64 for the optimal cut-off points. An analysis of human leucocyte antigen (HLA) haplotypes in SLE indicated that individuals with HLA-DQA1*01:01 and HLA-DQB1*05:01 were at a higher risk of being classified into the SLE group.
CONCLUSIONS
The use of PRSs to predict SLE enables the identification of high-risk patients before abnormal laboratory data were obtained or symptoms were manifested. Our findings underscore the potential of using PRSs and GWAS in identifying SLE markers, offering promise for early diagnosis and prediction of SLE.
Topics: Humans; Lupus Erythematosus, Systemic; Taiwan; Genome-Wide Association Study; Female; Genetic Predisposition to Disease; Male; Multifactorial Inheritance; Adult; Middle Aged; HLA-DQ alpha-Chains; Case-Control Studies; Antibodies, Antinuclear; HLA-DQ beta-Chains; Risk Factors; Haplotypes; Polymorphism, Single Nucleotide; Genetic Risk Score
PubMed: 38724181
DOI: 10.1136/lupus-2023-001035 -
Annals of Clinical and Translational... Jun 2024Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not...
OBJECTIVE
Comorbid anxiety occurs often in MS and is associated with disability progression. Polygenic scores offer a possible means of anxiety risk prediction but often have not been validated outside the original discovery population. We aimed to investigate the association between the Generalized Anxiety Disorder 2-item scale polygenic score with anxiety in MS.
METHODS
Using a case-control design, participants from Canadian, UK Biobank, and United States cohorts were grouped into cases (MS/comorbid anxiety) or controls (MS/no anxiety, anxiety/no immune disease or healthy). We used multiple anxiety measures: current symptoms, lifetime interview-diagnosed, and lifetime self-report physician-diagnosed. The polygenic score was computed for current anxiety symptoms using summary statistics from a previous genome-wide association study and was tested using regression.
RESULTS
A total of 71,343 individuals of European genetic ancestry were used: Canada (n = 334; 212 MS), UK Biobank (n = 70,431; 1,390 MS), and the USA (n = 578 MS). Meta-analyses identified that in MS, each 1-SD increase in the polygenic score was associated with ~50% increased odds of comorbid moderate anxious symptoms compared to those with less than moderate anxious symptoms (OR: 1.47, 95% CI: 1.09-1.99). We found a similar direction of effects in the other measures. MS had a similar anxiety genetic burden compared to people with anxiety as the index disease.
INTERPRETATION
Higher genetic burden for anxiety was associated with significantly increased odds of moderate anxious symptoms in MS of European genetic ancestry which did not differ from those with anxiety and no comorbid immune disease. This study suggests a genetic basis for anxiety in MS.
Topics: Humans; Multiple Sclerosis; Male; Female; Adult; Middle Aged; Multifactorial Inheritance; Comorbidity; Case-Control Studies; Anxiety Disorders; Anxiety; Canada; United States; United Kingdom; Aged; Genome-Wide Association Study; Genetic Predisposition to Disease
PubMed: 38715244
DOI: 10.1002/acn3.52025 -
Kidney International Reports May 2024Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite... (Review)
Review
Thousands of pathogenic variants in more than 100 genes can cause kidney cysts with substantial variability in phenotype and risk of subsequent kidney failure. Despite an established genotype-phenotype correlation in cystic kidney diseases, incomplete penetrance and variable disease expressivity are present as is the case in all monogenic diseases. In family members with autosomal dominant polycystic kidney disease (ADPKD), the same causal variant is responsible in all affected family members; however, there can still be striking discordance in phenotype severity. This narrative review explores contributors to within-family discordance in ADPKD severity. Cases of biallelic and digenic inheritance, where 2 rare pathogenic variants in cystogenic genes are coexistent in one family, account for a small proportion of within-family discordance. Genetic background, including cis and trans factors and the polygenic propensity for comorbid disease, also plays a role but has not yet been exhaustively quantified. Environmental exposures, including diet; smoking; alcohol, salt, and protein intake, and comorbid diseases, including obesity, diabetes, hypertension, kidney stones, dyslipidemia, and additional coexistent kidney diseases all contribute to ADPKD phenotypic variability among family members. Given that many of the factors contributing to phenotype variability are preventable, modifiable, or treatable, health care providers and patients need to be aware of these factors and address them in the treatment of ADPKD.
PubMed: 38707833
DOI: 10.1016/j.ekir.2024.01.053 -
American Journal of Human Genetics Jun 2024We present shaPRS, a method that leverages widespread pleiotropy between traits or shared genetic effects across ancestries, to improve the accuracy of polygenic scores....
We present shaPRS, a method that leverages widespread pleiotropy between traits or shared genetic effects across ancestries, to improve the accuracy of polygenic scores. The method uses genome-wide summary statistics from two diseases or ancestries to improve the genetic effect estimate and standard error at SNPs where there is homogeneity of effect between the two datasets. When there is significant evidence of heterogeneity, the genetic effect from the disease or population closest to the target population is maintained. We show via simulation and a series of real-world examples that shaPRS substantially enhances the accuracy of polygenic risk scores (PRSs) for complex diseases and greatly improves PRS performance across ancestries. shaPRS is a PRS pre-processing method that is agnostic to the actual PRS generation method, and as a result, it can be integrated into existing PRS generation pipelines and continue to be applied as more performant PRS methods are developed over time.
Topics: Multifactorial Inheritance; Humans; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Models, Genetic; Computer Simulation; Genetic Pleiotropy; Phenotype
PubMed: 38703768
DOI: 10.1016/j.ajhg.2024.04.009