Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD

Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤ -2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.     

Dissociation following traumatic medical treatment procedures in childhood: a longitudinal follow-up

Chronic illnesses often involve repeated hospitalization and invasive treatment procedures that can have a traumatic impact on child development. To explore possible consequences of treatment procedures, three groups of patients with congenital anomalies were examined longitudinally. At first admission, adolescents (ages 10-20, mean 15) with anorectal anomalies (n = 14), adolescents with Hirschsprung disease (n = 14), and hospitalized controls (n = 14) were assessed for treatment procedures, somatic function, mental health, and dissociative experiences. The assessment included the Adolescent Dissociative Experiences Scale (A-DES). At 10-year follow-up, the patients completed the Dissociative Experiences Scale (DES) and the Somatoform Dissociative Questionnaire (SDQ-20). Anal dilatation, an invasive medical treatment procedure performed daily by the parents the first 4 years, was correlated with the frequency and severity of persisting dissociative symptomatology. The procedure was the only significant predictor of A-DES and SDQ-20 scores, and one of two significant predictors of DES scores. This "experiment of nature" permitted a specific and unique opportunity to examine the impact of early traumatic exposure on child development in the absence of parental malevolence, and on later dissociative outcome in adolescence and adulthood. The findings might be valuable theoretically to our understanding of the development of psychopathology, and may lend itself for comparison with data on sexually abused children.     

Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants. © 2011 Wiley‐Liss, Inc.     

Genetic susceptibility to SLE: Recent progress from GWAS

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component, characterized by hyperactive T and B cells, autoantibody production, immune complex deposition and multi-organ damage. It affects predominantly women of child-bearing age and has population differences in both disease prevalence and severity. Genetic factors are known to play key roles in the disease through the use of association and family studies. Previously, SLE susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Since 2008, our understanding of the genetic basis of SLE has been rapidly advanced through genome-wide association studies (GWASs). More than 40 robust susceptibility loci have been identified and conformed to be associated with SLE using this technique. Most of these associated genes productions participate in important pathways involved in the pathogenesis of SLE, such as immune complex processing, toll-like receptor signaling, type I interferon production, and so on. A number of susceptibility loci with unknown functions in the pathogenesis of SLE have also been identified, indicating that additional molecular mechanisms contribute to the risk of developing SLE. It is noteworthy that susceptibility loci of SLE are shared by other immune-related diseases. Thus, common molecular pathways may be involved in the pathogenesis of these diseases. In this review, we summarize the key loci, achieving genome-wide significance, which have been shown to predispose to SLE. Analysis of relevant molecular pathways suggests new etiologic clues to SLE development. These genetic loci may help building the foundation for genetic diagnosis and personalized treatment for patients with SLE in the near future. However, substantial additional studies, including functional and gene-targeted studies, are required to confirm the causality of the genetic variants and their biological relevance in SLE development.     

Developmental outcome in Pierre Robin sequence: A longitudinal and prospective study of a consecutive series of severe phenotypes

Pierre Robin sequence (PRS) is a congenital condition with a heterogeneous and imprecise developmental prognosis. We conducted a longitudinal prospective study analyzing the long‐term developmental outcome of a consecutive series of 39 children with PRS who had an a priori good prognosis (isolated PRS or PRS associated with a Stickler syndrome) but severe neonatal disorders (respiratory and feeding difficulties). Psychomotor and cognitive levels, speech, and eating behavior were assessed at 15 months of age and 3 and 6 years of age; 24 of the oldest children were interviewed at age 11 or 12 years. Results were analyzed by diagnosis, extent of respiratory and feeding disorders, and treatment modalities. Cognitive scores were within normal ranges and increased over time, from 90.5 at 15 months of age to 109.1 at 6 years. The 24 oldest children were enrolled in the appropriate junior high school grade at the normal age. For children 15 months of age, language scores were below the average, as were scores for vocabulary at 3 years for half of the patients. At 6 years, children's speech showed persistent rhinolalia, which was mild (47%), moderate (11%), or major (11%). At 15 months of age, 74% of the children had satisfactory eating behavior, and 15% had serious difficulties. At 3 and 6 years, 18% and 6% of the children, respectively, had eating problems. Treatment modalities had no significant effect on long‐term outcome. Global developmental quotient scores were lower but not significantly for children with an associated Stickler syndrome than those with isolated PRS. Children with isolated PRS showed good prognosis. © 2013 Wiley Periodicals, Inc.     

Transethnic differences in GWAS signals: A simulation study

Genome‐wide association studies (GWASs) have allowed researchers to identify thousands of single nucleotide polymorphisms (SNPs) and other variants associated with particular complex traits. Previous studies have reported differences in the strength and even the direction of GWAS signals across different populations. These differences could be due to a combination of (1) lack of power, (2) allele frequency differences, (3) linkage disequilibrium (LD) differences, and (4) true differences in causal variant effect sizes. To determine whether properties (1)–(3) on their own might be sufficient to explain the patterns previously noted in strong GWAS signals, we simulated case–control data of European, Asian and African ancestry, applying realistic allele frequencies and LD from 1000 Genomes data but enforcing equal causal effect sizes across populations. Much of the observed differences in strong GWAS signals could indeed be accounted for by allele frequency and LD differences, enhanced by the Euro‐centric SNP bias and lower SNP coverage found in older GWAS panels. While we cannot rule out a role for true transethnic effect size differences, our results suggest that strong causal effects may be largely shared among human populations, motivating the use of transethnic data for fine‐mapping.     

Secular change in running performance of Japanese adolescents: A longitudinal developmental study

A 5-year longitudinal cohort study of the running development of Japanese adolescents was conducted at a secondary school in Tokyo from 1968 to 1994. The purpose was to investigate changes in the pattern of development over time. The test items were an endurance run (1,500 m for boys and 1,000 m for girls) and a dash (50 m for both sexes). The total number of subjects was 512 boys and 516 girls in the endurance run, and 825 boys and 895 girls in the dash. These students entered the first grade of the school from 1968 to 1989 at the age of 12 years, and were followed for the next 5 years. In the analyses, a quadratic regression model was used to characterize intra-individual, age-related changes in running performance. The model fit the observed data, and the validity of the model was confirmed. Secular changes in the running development of boys were minimal over the last 30 years. Changes in girls, however, had three different patterns: 1) an overall decrease in performance with an almost unchanged estimated performance in the first grade, 2) a greater decrease in the late-teenage years, and 3) a decrease in the age of maximal performance. Secular changes in physical growth (stature and body mass index) could not fully explain the secular changes in the running development of girls, suggesting that the underlying causes may be social and cultural. Am. J. Hum. Biol. 10:765–779, 1998. © 1998 Wiley-Liss, Inc.     

GWAS reveals new recessive loci associated with non-syndromic facial clefting

We have applied a GWAS to 40 consanguineous families segregating cases of non-syndromic cleft lip with or without cleft palate (NS CL/P) (a total of 160 affected and unaffected individuals) in order to trace potential recessive loci that confer susceptibility to this common facial malformation. Pedigree-based association test (PBAT) analyses reported nominal evidence of association and linkage over SNP markers located at 11q25 (rs4937877, P = 2.7 × 10⁻⁶), 19p12 (rs4324267, P = 1.6 × 10⁻⁵), 5q14.1 (rs4588572, P-value = 3.36 × 10⁻⁵), and 15q21.1 (rs4774497, P = 1.08 × 10⁻⁴). Using the Versatile Gene-Based Association Study to complement the PBAT results, we found clusters of markers located at chromosomes 19p12, 11q25, and 8p23.2 overcome the threshold for GWAS significance (P < 1 × 10⁻⁷). From this study, new recessive loci implicated in NS CL/P include: B3GAT1, GLB1L2, ZNF431, ZNF714, and CSMD1, even though the functional association with the genesis of NS CL/P remains to be elucidated. These results emphasize the importance of using homogeneous populations, phenotypes, and family structures for GWAS combined with gene-based association analyses, and should encourage. other researchers to evaluate these genes on independent patient samples affected by NS CL/P.     

Genetic architecture of adiposity measures among Asians: Findings from GWAS

Adiposity has gradually become a global public threat over the years with drastic increase in the attributable deaths and disability adjusted life years (DALYs). Given an increased metabolic risk among Asians as compared to Europeans for any given body mass index (BMI) and considering the differences in genetic architecture between them, the present review aims to summarize the findings from genome-wide scans for various adiposity indices and related anthropometric measures from Asian populations. The search for related studies, published till February 2022, were made on PubMed and GWAS Catalog using search strategy built with relevant keywords joined by Boolean operators. It was recorded that out of a total of 47 identified studies, maximum studies are from Korean population (n = 14), followed by Chinese (n = 7), and Japanese (n = 6). Nearly 200 loci have been identified for BMI, 660 for height, 16 for weight, 28 for circumferences (waist and hip), 32 for ratios (waist hip ratio [WHR] and thoracic hip ratio [THR]), 5 for body fat, 16 for obesity, and 28 for adiposity-related blood markers among Asians. It was observed that though, most of the loci were unique for each trait, there were 3 loci in common to BMI and WHR. Apart from validation of variants identified in European setting, there were many novel loci discovered in Asian populations. Notably, 125 novel loci form Asian studies have been reported for BMI, 47 for height, 5 for waist circumference, and 2 for adiponectin level to the existing knowledge of the genetic framework of adiposity and related measures. It is necessary to examine more advanced adiposity measures, specifically of relevance to abdominal adiposity, a major risk factor for cardiometabolic disorders among Asians. Moreover, in spite of being one continent, there is diversity among different ethnicities across Asia in terms of lifestyle, climate, geography, genetic structure and consequently the phenotypic manifestations. Hence, it is also important to consider ethnic specific studies for identifying and validating reliable genetic variants of adiposity measures among Asians.     

Using Genetic Marginal Effects to Study Gene-Environment Interactions with GWAS Data

Gene-environment interactions (GxE) play a central role in the theoretical relationship between genetic factors and complex traits. While genome wide GxE studies of human behaviors remain underutilized, in part due to methodological limitations, existing GxE research in model organisms emphasizes the importance of interpreting genetic associations within environmental contexts. In this paper, we present a framework for conducting an analysis of GxE using raw data from genome wide association studies (GWAS) and applying the techniques to analyze gene-by-age interactions for alcohol use frequency. To illustrate the effectiveness of this procedure, we calculate genetic marginal effects from a GxE GWAS analysis for an ordinal measure of alcohol use frequency from the UK Biobank dataset, treating the respondent’s age as the continuous moderating environment. The genetic marginal effects clarify the interpretation of the GxE associations and provide a direct and clear understanding of how the genetic associations vary across age (the environment). To highlight the advantages of our proposed methods for presenting GxE GWAS results, we compare the interpretation of marginal genetic effects with an interpretation that focuses narrowly on the significance of the interaction coefficients. The results imply that the genetic associations with alcohol use frequency vary considerably across ages, a conclusion that may not be obvious from the raw regression or interaction coefficients. GxE GWAS is less powerful than the standard “main effect” GWAS approach, and therefore require larger samples to detect significant moderated associations. Fortunately, the necessary sample sizes for a successful application of GxE GWAS can rely on the existing and on-going development of consortia and large-scale population-based studies.

     

T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections

Common variable immunodeficiency disorders (CVID) are a group of heterogeneous conditions that have in common primary failure of B cell function, although numerous T cell abnormalities have been described, including reduced proliferative response and reduced regulatory T cells. This study compared the T cell phenotype of CVID patients subdivided into clinical phenotypes as well as patients with partial antibody deficiencies [immunoglobulin (Ig)G subclass deficiency and selective IgA deficiency], X-linked agammaglobulinaemia (XLA) and healthy and disease controls. Absolute numbers of T cell subpopulations were measured by four-colour flow cytometry: naive T cells, central and effector memory and terminally differentiated (TEM) T cells, using CD45RA and CCR7 expression. Early, intermediate and late differentiation status of T cells was measured by CD27/CD28 expression. Putative follicular T cells, recent thymic emigrants and regulatory T cells were also assessed. Significant reduction in naive CD4 T cells, with reduced total CD4 and recent thymic emigrant numbers, was observed in CVID patients, most pronounced in those with autoimmune cytopenias or polyclonal lymphoproliferation. These findings suggest a lack of replenishment by new thymically derived cells. CD8 naive T cells were reduced in CVID patients, most significantly in the autoimmune cytopenia subgroup. There was a reduction in early differentiated CD4 and CD8 T cells and increased CD8 TEM in the CVID patients, particularly autoimmune cytopenia and polyclonal lymphoproliferation subgroups, suggesting a more activated T cell phenotype, due perhaps to an antigen-driven process. XLA patients had significantly reduced putative follicular T cells, which may depend on B cells for survival, while no significant alterations were observed in the T cells of those with IgG subclass deficiency or selective IgA deficiency.     

GW-SEM 2.0: Efficient,Flexible, and Accessible Multivariate GWAS

Behavior Genetics - Most genome-wide association study (GWAS) analyses test the association between single-nucleotide polymorphisms (SNPs) and a single trait or outcome. While valuable second-step...     

Familial hypercholesterolemia: A complex genetic disease with variable phenotypes

Familial hypercholesterolemia (FH) is the most frequent genetic disease and is characterized by elevation of LDL-cholesterol that accumulates in tissues leading to premature atherosclerosis and sometime tendon xanthomas. Main causes of FH are pathogenic variants in the genes encoding the LDL receptor (LDLR), its ligand - the apolipoprotein B (APOB) - or Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Rarer causes include variants in genes encoding apolipoprotein E (APOE) and the signal-transducing adaptor family member 1 (STAP1).Genetics of FH is extremely complicated by 1. high heterogeneity, 2. presence of variant clusters and 3. phenotypic variability. In fact, a great variability was observed among patients with the same genetic status: an overlap of LDL-cholesterol levels was observed between heterozygous patients (HeFH) and homozygous FH patients, as well as some HeFH showed a normal lipid profile. A correct pathogenicity evaluation is the first step to correctly define the genetic status helping to identify the variants which really cause the FH.Several phenotypic differences were observed among HeFH patients carrying different variant types (null or defective) or variants in different affected genes. Patients with a null variant in LDLR gene showed higher LDL-cholesterol levels and higher risk for coronary artery disease than patients with a defective variant. Pathogenic variants in several lipid-related genes causing different dyslipidemias were found among FH patients acting as both modifying factors (worsening the phenotype) and confounding factors (needing a differential diagnosis to be discriminated from FH). This review aims at depicting the complex genetic basis of FH.     

Effects of pre-cooling procedures on intermittent-sprint exercise performance in warm conditions

The aim of this study was to determine whether pre-cooling procedures improve both maximal sprint and sub-maximal work during intermittent-sprint exercise. Nine male rugby players performed a familiarisation session and three testing sessions of a 2 × 30-min intermittent sprint protocol, which consisted of a 15-m sprint every min separated by free-paced hard-running, jogging and walking in 32°C and 30% humidity. The three sessions included a control condition, Ice-vest condition and Ice-bath/Ice-vest condition, with respective cooling interventions imposed for 15-min pre-exercise and 10-min at half-time. Performance measures of sprint time and % decline and distance covered during sub-maximal exercise were recorded, while physiological measures of core temperature (T _core), mean skin temperature (T _skin), heart rate, heat storage, nude mass, rate of perceived exertion, rate of thermal comfort and capillary blood measures of lactate [La⁻], pH, Sodium (Na⁺) and Potassium (K⁺) were recorded. Results for exercise performance indicated no significant differences between conditions for the time or % decline in 15-m sprint efforts or the distance covered during sub-maximal work bouts; however, large effect size data indicated a greater distance covered during hard running following Ice-bath cooling. Further, lowered T _core, T _skin, heart rate, sweat loss and thermal comfort following Ice-bath cooling than Ice-vest or Control conditions were present, with no differences present in capillary blood measures of [La⁻], pH, K⁺ or Na⁺. As such, the ergogenic benefits of effective pre-cooling procedures in warm conditions for team-sports may be predominantly evident during sub-maximal bouts of exercise.     

Discovery of genomic loci associated with sleep apnea risk through multi-trait GWAS analysis with snoring

Study ObjectivesDespite its association with severe health conditions, the etiology of sleep apnea (SA) remains understudied. This study sought to identify genetic variants robustly associated with SA risk.MethodsWe performed a genome-wide association study (GWAS) meta-analysis of SA across five cohorts (N_Total = 523 366), followed by a multi-trait analysis of GWAS (multi-trait analysis of genome-wide association summary statistics [MTAG]) to boost power, leveraging the high genetic correlation between SA and snoring. We then adjusted our results for the genetic effects of body mass index (BMI) using multi-trait-based conditional and joint analysis (mtCOJO) and sought replication of lead hits in a large cohort of participants from 23andMe, Inc (N_Total = 1 477 352; N_cases = 175 522). We also explored genetic correlations with other complex traits and performed a phenome-wide screen for causally associated phenotypes using the latent causal variable method.ResultsOur SA meta-analysis identified five independent variants with evidence of association beyond genome-wide significance. After adjustment for BMI, only one genome-wide significant variant was identified. MTAG analyses uncovered 49 significant independent loci associated with SA risk. Twenty-nine variants were replicated in the 23andMe GWAS adjusting for BMI. We observed genetic correlations with several complex traits, including multisite chronic pain, diabetes, eye disorders, high blood pressure, osteoarthritis, chronic obstructive pulmonary disease, and BMI-associated conditions.ConclusionOur study uncovered multiple genetic loci associated with SA risk, thus increasing our understanding of the etiology of this condition and its relationship with other complex traits.     

An evaluation of statistical procedures for comparing an individual's performance with that of a group of controls

The single case methodology that is widely used in cognitive neuropsychology often requires a comparison of data from a single individual (the patient) with that from a group of controls, in order to ascertain whether the patient's mean score can be viewed as significantly different from that of controls. This article reviews methods that have been used to deal with such data. Although Analysis of Variance (ANOVA) provides one possible solution of comparing group means, unequal group sizes and differences in variability between patient and controls can violate the assumptions of the test. Using Monte Carlo simulations, it was found that differences in group size and a group of N = 1 did not significantly affect the reliability of the analysis. In contrast, unacceptably high Type I errors were obtained when, in addition to unequal group sizes, there were relatively modest differences between the variance of the patient and that of the controls. We suggest that ANOVA can be used for the comparison of the mean score of an individual with that of a group of controls, but that when there is a difference in variability between the two groups, revised F criteria should be used in order to make the analysis reliable. A table of modified F values is given, which can be used for various departures from homogeneity of variance.