Multi-ancestry Genome Wide Association Study Meta-analysis of Non-syndromic Orofacial Clefts.

Non-syndromic orofacial clefts (NSOC) are common craniofacial birth defects, and result from both genetic and environmental factors. NSOC include three major sub-phenotypes: non-syndromic cleft lip with palate (NSCLP), non-syndromic cleft lip only (NSCLO) and non-syndromic cleft palate only (NSCPO), NSCLP and NSCLO are also sometimes grouped as non-syndromic cleft lip with or without cleft palate (NSCL/P) based on epidemiology. Currently known loci only explain a limited proportion of the heritability of NSOC.

DeepFace: Deep-learning-based framework to contextualize orofacial-cleft-related variants during human embryonic craniofacial development.

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown.

Effects of the valsartan recall on heart failure patients: A nationwide analysis.

Background: Valsartan is commonly used for cardiac conditions. In 2018, the Food and Drug Administration recalled generic valsartan due to the detection of impurities. Our objective was to determine if heart failure patients receiving valsartan at the recall date had a greater likelihood of unfavorable outcomes than patients using comparable antihypertensives.

A Retrospective Cohort Study of the 2018 Angiotensin Receptor Blocker Recalls and Subsequent Drug Shortages in Patients With Hypertension.

Background: Valsartan was recalled by the US Food and Drug Administration in July 2018 for carcinogenic impurities, resulting in a drug shortage and management challenges for valsartan users. The influence of the valsartan recall on clinical outcomes is unknown. We compared the risk of adverse events between hypertensive patients using valsartan and a propensity score-matched group using nonrecalled angiotensin receptor blockers and angiotensin-converting enzyme inhibitors.

Association of Early Childhood Caries with Bitter Taste Receptors: A Meta-Analysis of Genome-Wide Association Studies and Transcriptome-Wide Association Study.

Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.

Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately.

Genome-Wide Association Study of Non-syndromic Orofacial Clefts in a Multiethnic Sample of Families and Controls Identifies Novel Regions.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle (~1/800 and 1/900, respectively).

Cleft lip/palate and educational attainment: cause, consequence or correlation? A Mendelian randomization study.

Background: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life.

Individuals with nonsyndromic orofacial clefts have increased asymmetry of fingerprint patterns.

Dermatoglyphic patterns on the fingers often differ in syndromes and other conditions with a developmental component, compared to the general population. Previous literature on the relationship between orofacial clefts-the most common craniofacial birth defect in humans-and dermatoglyphics is inconsistent, with some studies reporting altered pattern frequencies and/or increased asymmetry and others failing to find differences. To investigate dermatoglyphics in orofacial clefting, we obtained dermatoglyphic patterns in a large multiethnic cohort of orofacial cleft cases (N = 367), their unaffected family members (N = 836), and controls (N = 299).

Effects of genotype on TENS effectiveness in controlling knee pain in persons with mild to moderate osteoarthritis.

Background: This study examined the extent to which genetic variability modifies Transcutaneous Electrical Nerve Stimulation (TENS) effectiveness in osteoarthritic knee pain.

Methods: Seventy-five participants with knee osteoarthritis were randomly assigned to either: (a) High-frequency TENS, (b) Low-frequency TENS or (c) Transient Placebo TENS. Pain measures were collected pre- and post-treatment.

Novel caries loci in children and adults implicated by genome-wide analysis of families.

Background: Dental caries is a common chronic disease among children and adults alike, posing a substantial health burden. Caries is affected by multiple genetic and environmental factors, and prior studies have found that a substantial proportion of caries susceptibility is genetically inherited.

Methods: To identify such genetic factors, we conducted a genome-wide linkage scan in 464 extended families with 2616 individuals from Iowa, Pennsylvania and West Virginia for three dental caries phenotypes: (1) PRIM: dichotomized as zero versus one or more affected primary teeth, (2) QTOT1: age-adjusted quantitative caries measure for both primary and permanent dentitions including pre-cavitated lesions, and (3) QTOT2: age-adjusted quantitative caries excluding pre-cavitated lesions.

Identifying genetic risk loci for diabetic complications and showing evidence for heterogeneity of type 1 diabetes based on complications risk.

There is a growing body of evidence suggesting that type 1 diabetes (T1D) is a genetically heterogeneous disease. However, the extent of this heterogeneity, and what observations may distinguish different forms, is unclear. One indicator may be T1D-related microvascular complications (MVCs), which are familial, but occur in some families, and not others.

A Pipeline for Classifying Relationships Using Dense SNP/SNV Data and Putative Pedigree Information.

When genome-wide association studies (GWAS) or sequencing studies are performed on family-based datasets, the genotype data can be used to check the structure of putative pedigrees. Even in datasets of putatively unrelated people, close relationships can often be detected using dense single-nucleotide polymorphism/variant (SNP/SNV) data. A number of methods for finding relationships using dense genetic data exist, but they all have certain limitations, including that they typically use average genetic sharing, which is only a subset of the available information.

Mega2: validated data-reformatting for linkage and association analyses.

Background: In a typical study of the genetics of a complex human disease, many different analysis programs are used, to test for linkage and association. This requires extensive and careful data reformatting, as many of these analysis programs use differing input formats. Writing scripts to facilitate this can be tedious, time-consuming, and error-prone.

Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21.

In oocytes with nondisjoined chromosomes 21 due to a meiosis I (MI) error, recombination is significantly reduced along chromosome 21; several lines of evidence indicate that this contributes to the nondisjunction event. A pilot study found evidence that these oocytes also have reduced recombination genome-wide when compared with controls. This suggests that factors that act globally may be contributing to the reduced recombination on chromosome 21, and hence, the nondisjunction event.

Two-dimensional linkage analyses of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multifactorial disease with complex genetic etiology, about which little is known. Here, we apply a two-stage procedure in which a quick first-stage analysis was used to narrow down targets for a more thorough and detailed testing for gene x gene interaction. Potentially interesting regions were first identified by testing for major gene effects using non-parametric linkage methods.

Robust score statistics for QTL linkage analysis.

The traditional variance components approach for quantitative trait locus (QTL) linkage analysis is sensitive to violations of normality and fails for selected sampling schemes. Recently, a number of new methods have been developed for QTL mapping in humans. Most of the new methods are based on score statistics or regression-based statistics and are expected to be relatively robust to non-normality of the trait distribution and also to selected sampling, at least in terms of type I error.

Discussing gene-gene interaction: warning--translating equations to English may result in jabberwocky.

Interest in mapping susceptibility alleles for complex diseases, which do not follow a classic single-gene segregation pattern, has driven interest in methods that account for, or use information from one locus when mapping another. Our discussion group examined methods related to epistasis or gene x gene interaction. The goal of modeling gene x gene interaction varied across groups; some papers tried to detect gene x gene interaction while others tried to exploit it to map genes.

Analysis of alcohol dependence phenotype in the COGA families using covariates to detect linkage.

Linkage analysis methods that incorporate etiological heterogeneity of complex diseases are likely to demonstrate greater power than traditional linkage analysis methods. Several such methods use covariates to discriminate between linked and unlinked pedigrees with respect to a certain disease locus. Here we apply several such methods including two mixture models, ordered subset analysis, and a conditional logistic model to genome scan data on the DSM-IV alcohol dependence phenotype on the Collaborative Studies on Genetics of Alcoholism families, and compare the results to traditional nonparametric linkage analysis.

Comparative study of multipoint methods for genotype error detection.

Several programs are currently available for the detection of genotyping error that may or may not be Mendelianly inconsistent. However, no systematic study exists that evaluates their performance under varying pedigree structures and sizes, marker spacing, and allele frequencies. Our simulation study compares four multipoint methods: Merlin, Mendel4, SimWalk2, and Sibmed.

Mega2: data-handling for facilitating genetic linkage and association analyses.

Unlabelled: Mega2, the manipulation environment for genetic analysis, transparently allows users to process genetic data for family-based or case/control studies accurately and efficiently. In addition to data validation checks, Mega2 provides analysis setup capabilities for a broad choice of commonly used genetic analysis programs, including SimWalk2, ASPEX, GeneHunter, SLINK, SIMULATE, S.A.