GENLIB: new function to simulate haplotype transmission in large complex genealogies.

SUMMARY: Founder populations with deep genealogical data are well suited for investigating genetic variants contributing to diseases. Here, we present a major update of the genealogical analysis R package GENLIB, centered around a new function which can simulate the transmission of haplotypes from founders to probands along very large and complex user-specified genealogies. AVAILABILITY AND IMPLEMENTATION: The latest update of the GENLIB package (v1.1.9) contains the new gen.simuHaplo() function and is available on the CRAN repository and from https://github.com/R-GENLIB/GENLIB. Examples can be accessed at https://github.com/R-GENLIB/simuhaplo_functions.

Genome-wide association study of age at menarche in the Taiwan Biobank suggests NOL4 as a novel associated gene.

Sexual maturation is a complex physiological process that involves multiple variables, such as genetic and environmental factors. Among females, age at menarche (AM) is a critical milestone for sexual maturation. This study aimed to identify genetic markers of AM using nationwide population cohort data in Taiwan. Females with self-reported AM between 10 and 16 years (N = 39,827) were eligible for the final analysis. To identify genetic signals related to AM, we conducted a genome-wide association study using a linear regression model and split-half meta-analysis method to verify our findings. The Functional Mapping and Annotation web-based platform was used for positional mapping and gene-based and gene-set analyses. The meta-analysis identified four significant loci, i.e., LIN28B (pooled P = 1.39 × 10-21), NOL4 (pooled P = 8.94 × 10-9), GPR45 (pooled P = 4.19 × 10-11), and LOC105373831 (pooled P = 4.37 × 10-8), that were associated with AM. MAGMA gene-based analysis revealed that LIN28B (P = 1.13 × 10-8), NOL4 (P = 2.27 × 10-7), RXRG (P = 4.34 × 10-7), ETV5 (P = 1.75 × 10-6), and HACE1 (P = 1.82 × 10-6) were significantly associated with AM, while the gene-set analysis identified a significantly enriched pathway involving mTOR signaling complex (FDR corrected P = 1.28 × 10-2). The results replicated evidence for several genetic markers associated with AM in the Taiwanese female population. Our analysis identified a novel locus (rs7239368) in NOL4 associated with AM (ß = 0.051 ± 0.009 years, pooled P = 8.94 × 10-9), whereas additional research is needed to validate its molecular role in sexual maturation.

The impact of fast food marketing on brand preferences and fast food intake of youth aged 10-17 across six countries.

BACKGROUND: Consumption of fast food, which is associated with poor diet, weight gain and the development of noncommunicable diseases, is high amongst youth. Fast food marketing, a modifiable determinant of excess weight and obesity, affects youth's food-related behaviours. This study aimed to examine the relationship between exposure to fast food marketing and the fast food brand preferences and intake amongst youth aged 10-17 across six countries. METHODS: Data from 9,695 youth respondents living in Australia, Canada, Chile, Mexico, the United Kingdom (UK) and the United States (US) were analyzed from the 2019 International Food Policy Study (IFPS) Youth Survey. Survey measures assessed exposure to fast food marketing and brand-specific marketing, and preference for these brands and fast food intake. Regression models adjusted for age, sex, income adequacy and ethnicity were used to examine the associations. RESULTS: Exposure to fast food marketing was positively associated with brand preferences and intake consistently across most countries. Overall, preference for McDonald's (OR:1.97; 95% CI:1.52, 2.56), KFC (OR:1.61; 95% CI:1.24, 2.09) and Subway (OR:1.73; 95% CI:1.34, 2.24) were highest when exposed to general fast food marketing ≥ 2x/week compared to never. Preference for McDonald's (OR:2.32; 95% CI:1.92, 2.79), KFC (OR:2.28; 95% CI:1.95, 2.68) and Subway (OR:2.75; 95% CI:2.32, 3.27) were also higher when exposed to marketing for each brand compared to not. Fast food intake was highest in Chile (IRR:1.90; 95% CI:1.45, 2.48), the UK (IRR:1.40; 95% CI:1.20, 1.63), Canada (IRR:1.32; 95% CI:1.19, 1.48), Mexico (IRR:1.26; 95% CI:1.05, 1.53) and the US (IRR:1.21; 95% CI:1.05, 1.41) when exposed to general fast food marketing ≥ 2x/week compared to never and was higher across most countries when exposed to brand-specific marketing compared to not. Respondents classified as ethnic minorities were more likely to report consuming fast food than ethnic majorities, and females were less likely to report consuming fast food than males. CONCLUSIONS: Exposure to fast food marketing is consistently and positively associated with brand preferences and fast food intake in all six countries. Our results highlight the need for strict government regulation to reduce exposure of unhealthy food marketing to youth in all six countries.

Comparison of mixed model based approaches for correcting for population substructure with application to extreme phenotype sampling.

BACKGROUND: Mixed models are used to correct for confounding due to population stratification and hidden relatedness in genome-wide association studies. This class of models includes linear mixed models and generalized linear mixed models. Existing mixed model approaches to correct for population substructure have been previously investigated with both continuous and case-control response variables. However, they have not been investigated in the context of extreme phenotype sampling (EPS), where genetic covariates are only collected on samples having extreme response variable values. In this work, we compare the performance of existing binary trait mixed model approaches (GMMAT, LEAP and CARAT) on EPS data. Since linear mixed models are commonly used even with binary traits, we also evaluate the performance of a popular linear mixed model implementation (GEMMA). RESULTS: We used simulation studies to estimate the type I error rate and power of all approaches assuming a population with substructure. Our simulation results show that for a common candidate variant, both LEAP and GMMAT control the type I error rate while CARAT's rate remains inflated. We applied all methods to a real dataset from a Québec, Canada, case-control study that is known to have population substructure. We observe similar type I error control with the analysis on the Québec dataset. For rare variants, the false positive rate remains inflated even after correction with mixed model approaches. For methods that control the type I error rate, the estimated power is comparable. CONCLUSIONS: The methods compared in this study differ in their type I error control. Therefore, when data are from an EPS study, care should be taken to ensure that the models underlying the methodology are suitable to the sampling strategy and to the minor allele frequency of the candidate SNPs.

General and abdominal obesity trajectories across adulthood, and risk of prostate cancer: results from the PROtEuS study, Montreal, Canada.

PURPOSE: Greater body fatness is a probable cause of advanced prostate cancer (PCa). Body fat distribution and timing of exposure may be relevant. We investigated associations between body size trajectories and PCa incidence in a population-based case-control study in Montreal, Canada. METHODS: Cases (n = 1,931), aged ≤ 75 years, were diagnosed with PCa in 2005-2009; 1,994 controls were selected from the electoral list. Interviews were conducted to assess body mass index (BMI) and Stunkard's silhouette at ages 20, 40, 50, 60 years, and before interview. Current waist and hip circumferences were measured, and a predictive model estimated waist circumference in the past. BMI and waist circumference trajectories were determined to identify subgroups. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for the association between anthropometric indicators and PCa. RESULTS: Subjects with a current BMI ≥ 30 kg/m2 had a lower risk of overall PCa (OR 0.71, 95% CI 0.59-0.85). Associations with adult BMI followed similar trends for less and more aggressive tumors, with stronger inverse relationships in early adulthood. Contrastingly, current waist circumference ≥ 102 cm was associated with elevated risk of high-grade PCa (OR 1.33, 95% CI 1.03-1.71). Men with increasing BMI or waist circumference adult trajectories had a lower risk of PCa, especially low-grade, than those in the normal-stable range. This was especially evident among men in the obese-increase group for BMI and waist circumference. CONCLUSION: Abdominal obesity increased the risk of aggressive PCa. The inverse relationship between body size trajectories and PCa may reflect PSA hemodilution, lower detection, and/or a true etiological effect.

Age-Related Eye Disease and Cognitive Function: The Search for Mediators.

PURPOSE: Age-related eye disease may be associated with cognitive decline, but the scientific literature has not been consistent. Furthermore, no studies have been able to explain the relationship. Our objective was to assess whether older adults with age-related macular degeneration (AMD) or glaucoma performed worse on 6 cognitive tests compared with older adults with normal vision and, if so, to understand why. DESIGN: Cross-sectional analysis of hospital-based study (Maisonneuve-Rosemont Hospital Ophthalmology Clinics, Montréal, Canada). PARTICIPANTS: Three hundred thirty-six adults 65 years of age or older with either AMD, glaucoma, or normal vision. METHODS: Cognition was measured with 6 cognitive tests administered orally. Activity levels were measured using the Victoria Longitudinal Study Activity Lifestyle Questionnaire. Visual acuity and visual field were measured. Multiple linear regression was used. Mediation was assessed using structural equation modeling. MAIN OUTCOME MEASURES: Results of the verbal fluency test (animal and letter versions), the digit span test (forward and backward versions), and the logical memory test (immediate and delayed recall). RESULTS: People with glaucoma showed lower scores on 3 cognitive tests than the group with normal vision: the digit span forward and backward tests (ß = -0.8 [95% confidence interval (CI), -1.5 to -0.2] and ß = -0.7 [95% CI, -1.3 to -0.1], respectively) and the logical memory test with immediate recall (ß = -1.3 [95% CI, -2.4 to -0.2]). Activity levels statistically significantly mediated the relationship between glaucoma and the digit span forward test (P = 0.043; percentage of the total effect mediated, 17%). CONCLUSIONS: People with glaucoma showed lower scores on cognitive tests that may depend on verbal working memory and encoding. If confirmed in longitudinal studies, interventions should be developed that are appropriate for a visually impaired population to slow this cognitive decline.

Modeling gene-environment interactions in longitudinal family studies: a comparison of methods and their application to the association between the IGF pathway and childhood obesity.

BACKGROUND: The interactive effect of the IGF pathway genes with the environment may contribute to childhood obesity. Such gene-environment interactions can take on complex forms. Detecting those relationships using longitudinal family studies requires simultaneously accounting for correlations within individuals and families. METHODS: We studied three methods for detecting interaction effects in longitudinal family studies. The twin model and the nonparametric partition-based score test utilized individual outcome averages, whereas the linear mixed model used all available longitudinal data points. Simulation experiments were performed to evaluate the methods' power to detect different gene-environment interaction relationships. These methods were applied to the Quebec Newborn Twin Study data to test for interaction effects between the IGF pathway genes (IGF-1, IGFALS) and environmental factors (physical activity, daycare attendance and sleep duration) on body mass index outcomes. RESULTS: For the simulated data, the twin model with the mean time summary statistic yielded good performance overall. Modelling an interaction as linear when the true model had a different relationship influenced power; for certain non-linear interactions, none of the three methods were effective. Our analysis of the IGF pathway genes showed suggestive association for the joint effect of IGF-1 variant at position 102,791,894 of chromosome 12 and physical activity. However, this association was not statistically significant after multiple testing correction. CONCLUSIONS: The analytical approaches considered in this study were not robust to different gene-environment interactions. Methodological innovations are needed to improve the current methods' performances for detecting non-linear interactions. More studies are needed in order to better understand the IGF pathway's role in childhood obesity development.

Characteristics and outcomes of antiretroviral-treated HIV-HBV co-infected patients in Canada?

BACKGROUND: Hepatitis B (HBV) and Human Immunodeficiency Virus (HIV) share common risk factors for exposure. Co-infected patients have an increased liver-related mortality risk and may have accelerated HIV progression. The epidemiology and demographic characteristics of HIV-HBV co-infection in Canada remain poorly defined. We compared the demographic and clinical characteristics and factors associated with advanced hepatic fibrosis between HIV and HIV-HBV co-infected patients. METHODS: A retrospective cohort analysis was conducted using data from the Canadian Observational Cohort (CANOC) Collaboration, including eight sites from British Columbia, Quebec, and Ontario. Eligible participants were HIV-infected patients who initiated combination ARV between January 1, 2000 and December 14, 2014. Demographic and clinical characteristics were compared between HIV-HBV co-infected and HIV-infected groups using chi-square or Fisher exact tests for categorical variables, and Wilcoxon's Rank Sum test for continuous variables. Liver fibrosis was estimated by the AST to Platelet Ratio Index (APRI). RESULTS: HBV status and APRI values were available for 2419 cohort participants. 199 (8%) were HBV co-infected. Compared to HIV-infected participants, HIV-HBV co-infected participants were more likely to use injection drugs (28% vs. 21%, p = 0.03) and be HCV-positive (31%, vs. 23%, p = 0.02). HIV-HBV co-infected participants had lower baseline CD4 T cell counts (188 cells/mm3, IQR: 120-360) compared to 235 cells/mm3 in HIV-infected participants (IQR: 85-294) (p = 0.0002) and higher baseline median APRI scores (0.50 vs. 0.37, p < 0.0001). This difference in APRI was no longer clinically significant at follow-up (0.32 vs. 0.30, p = 0.03). HIV-HBV co-infected participants had a higher mortality rate compared to HIV-infected participants (11% vs. 7%, p = 0.02). CONCLUSION: The prevalence, demographic and clinical characteristics of the HIV-HBV co-infected population in Canada is described. HIV-HBV co-infected patients have higher mortality, more advanced CD4 T cell depletion, and liver fibrosis that improves in conjunction with ARV therapy. The high prevalence of unknown HBV status demonstrates a need for increased screening among HIV-infected patients in Canada.

Utilization of key preventive measures for pregnancy complications and malaria among women in Jimma Zone, Ethiopia.

BACKGROUND: In Ethiopia, malaria infections and other complications during pregnancy contribute to the high burden of maternal morbidity and mortality. Preventive measures are available, however little is known about the factors influencing the uptake of maternal health services and interventions by pregnant women in Ethiopia. METHODS: We analyzed data from a community-based cross-sectional survey conducted in 2016 in three rural districts of Jimma Zone, Ethiopia, with 3784 women who had a pregnancy outcome in the year preceding the survey. We used multivariable logistic regression models accounting for clustering to identify the determinants of antenatal care (ANC) attendance and insecticide-treated net (ITN) ownership and use, and the prevalence and predictors of malaria infection among pregnant women. RESULTS: Eighty-four percent of interviewed women reported receiving at least one ANC visit during their last pregnancy, while 47% reported attending four or more ANC visits. Common reasons for not attending ANC included women's lack of awareness of its importance (48%), distance to health facility (23%) and unavailability of transportation (14%). Important determinants of ANC attendance included higher education level and wealth status, woman's ability to make healthcare decisions, and pregnancy intendedness. An estimated 48% of women reported owning an ITN during their last pregnancy. Of these, 55% reported to have always slept under it during their last pregnancy. Analysis revealed that the odds of owning and using ITNs were respectively 2.07 (95% CI: 1.62-2.63) and 1.73 (95% CI: 1.32-2.27) times higher among women who attended at least one ANC visit. The self-reported prevalence of malaria infection during pregnancy was low (1.4%) across the three districts. We found that young, uneducated, and unemployed women presented higher odds of malaria infection during their last pregnancy. CONCLUSION: ANC and ITN uptake during pregnancy in Jimma Zone fall below the respective targets of 95 and 90% set in the Ethiopian Health Sector Transformation Plan for 2020, suggesting that more intensive programmatic efforts still need to be directed towards improving access to these health services. Reaching ANC non-users and ITN ownership and use as part of ANC services could be emphasized to address these gaps.

Factors associated with human West Nile virus infection in Ontario: a generalized linear mixed modelling approach.

BACKGROUND: West Nile Virus (WNV) is a mosquito-borne pathogen that has become established in North America. Risk for human infection varies geographically in accordance with climate and population factors. Though often asymptomatic, human WNV infection can cause febrile illness or, rarely, neurologic disease. WNV has become a public health concern in Canada since its introduction in 2001. METHODS: To identify predictors of human WNV incidence at the public health unit (PHU) level in Ontario, Canada, we combined data on environmental and population characteristics of PHUs with historical mosquito and human surveillance records from 2002 to 2013. We examined the associations between annual WNV incidence and monthly climate indices (e.g. minimum and maximum temperature, average precipitation), land cover (e.g. deciduous forest, water), population structure (e.g. age and sex composition) and the annual percentage of WNV-positive mosquito pools from 2002 to 2013. We then developed a generalized linear mixed model with a Poisson distribution adjusting for spatial autocorrelation and repeat measures. Further to this, to examine potential 'early season' predictors of WNV incidence in a given year, we developed a model based on winter and spring monthly climate indices. RESULTS: Several climate indices, including mean minimum temperature (o C) in February (RR = 1.58, CI: [1.42, 1.75]), and the annual percentage of WNV-positive mosquito pools (RR = 1.07, CI: [1.04, 1.11]) were significantly associated with human WNV incidence at the PHU level. Higher winter minimum temperatures were also strongly associated with annual WNV incidence in the 'early season' model (e.g. February minimum temperature (RR = 1.91, CI: [1.73, 2.12]). CONCLUSIONS: Our study demonstrates that early season temperature and precipitation indices, in addition to the percentage of WNV-positive mosquito pools in a given area, may assist in predicting the likelihood of a more severe human WNV season in southern regions of Ontario, where WNV epidemics occur sporadically.

Survey highlights the need for specific interventions to reduce frequent conflicts between healthcare professionals providing paediatric end-of-life care.

AIMS: This study explored how paediatric healthcare professionals experienced and coped with end-of-life conflicts and identified how to improve coping strategies. METHODS: A questionnaire was distributed to all 2300 professionals at a paediatric university hospital, covering the frequency of end-of-life conflicts, participants, contributing factors, resolution strategies, outcomes and the usefulness of specific institutional coping strategies. RESULTS: Of the 946 professionals (41%) who responded, 466 had witnessed or participated in paediatric end-of-life discussions: 73% said these had led to conflict, more frequently between professionals (58%) than between professionals and parents (33%). Frequent factors included professionals' rotations, unprepared parents, emotional load, unrealistic parental expectations, differences in values and beliefs, parents' fear of hastening death, precipitated situations and uncertain prognosis. Discussions with patients and parents and between professionals were the most frequently used coping strategies. Conflicts were frequently resolved by the time of death. Professionals mainly supported designating one principal physician and nurse for each patient, two-step interdisciplinary meetings - between professionals then with parents - postdeath ethics meetings, bereavement follow-up protocols and early consultations with paediatric palliative care and clinical ethics services. CONCLUSION: End-of-life conflicts were frequent and predominantly occurred between healthcare professionals. Specific interventions could target most of the contributing factors.

Pathway-based association study of multiple candidate genes and multiple traits using structural equation models.

There is increasing interest in the joint analysis of multiple genetic variants from multiple genes and multiple correlated quantitative traits in association studies. The classical approach involves testing univariate associations between genotypes and phenotypes and correcting for multiple testing that results in loss of power to detect associations. In this paper, we propose modeling complex relationships between genetic variants in candidate genes and measured correlated traits using structural equation models (SEM), taking advantage of prior knowledge on clinical and genetic pathways. We adopt generalized structured component analysis (GSCA) as an approach to SEM and develop a single association test between multiple genetic variants in a gene and a set of correlated traits, taking into account all available data from other genes and other traits. The performance of this test is investigated by simulations. We apply the proposed method to the Quebec Child and Adolescent Health and Social Survey (1999) data to investigate genetic associations with cardiovascular disease-related traits.

GENLIB: an R package for the analysis of genealogical data.

BACKGROUND: Founder populations have an important role in the study of genetic diseases. Access to detailed genealogical records is often one of their advantages. These genealogical data provide unique information for researchers in evolutionary and population genetics, demography and genetic epidemiology. However, analyzing large genealogical datasets requires specialized methods and software. The GENLIB software was developed to study the large genealogies of the French Canadian population of Quebec, Canada. These genealogies are accessible through the BALSAC database, which contains over 3 million records covering the whole province of Quebec over four centuries. Using this resource, extended pedigrees of up to 17 generations can be constructed from a sample of present-day individuals. RESULTS: We have extended and implemented GENLIB as a package in the R environment for statistical computing and graphics, thus allowing optimal flexibility for users. The GENLIB package includes basic functions to manage genealogical data allowing, for example, extraction of a part of a genealogy or selection of specific individuals. There are also many functions providing information to describe the size and complexity of genealogies as well as functions to compute standard measures such as kinship, inbreeding and genetic contribution. GENLIB also includes functions for gene-dropping simulations. The goal of this paper is to present the full functionalities of GENLIB. We used a sample of 140 individuals from the province of Quebec (Canada) to demonstrate GENLIB's functions. Ascending genealogies for these individuals were reconstructed using BALSAC, yielding a large pedigree of 41,523 individuals. Using GENLIB's functions, we provide a detailed description of these genealogical data in terms of completeness, genetic contribution of founders, relatedness, inbreeding and the overall complexity of the genealogical tree. We also present gene-dropping simulations based on the whole genealogy to investigate identical-by-descent sharing of alleles and chromosomal segments of different lengths and estimate probabilities of identical-by-descent sharing. CONCLUSIONS: The R package GENLIB provides a user friendly and flexible environment to analyze extensive genealogical data, allowing an efficient and easy integration of different types of data, analytical methods and additional developments and making this tool ideal for genealogical analysis.

Identifying risk profiles for childhood obesity using recursive partitioning based on individual, familial, and neighborhood environment factors.

BACKGROUND: Few studies consider how risk factors within multiple levels of influence operate synergistically to determine childhood obesity. We used recursive partitioning analysis to identify unique combinations of individual, familial, and neighborhood factors that best predict obesity in children, and tested whether these predict 2-year changes in body mass index (BMI). METHODS: Data were collected in 2005-2008 and in 2008-2011 for 512 Quebec youth (8-10 years at baseline) with a history of parental obesity (QUALITY study). CDC age- and sex-specific BMI percentiles were computed and children were considered obese if their BMI was ≥95th percentile. Individual (physical activity and sugar-sweetened beverage intake), familial (household socioeconomic status and measures of parental obesity including both BMI and waist circumference), and neighborhood (disadvantage, prestige, and presence of parks, convenience stores, and fast food restaurants) factors were examined. Recursive partitioning, a method that generates a classification tree predicting obesity based on combined exposure to a series of variables, was used. Associations between resulting varying risk group membership and BMI percentile at baseline and 2-year follow up were examined using linear regression. RESULTS: Recursive partitioning yielded 7 subgroups with a prevalence of obesity equal to 8%, 11%, 26%, 28%, 41%, 60%, and 63%, respectively. The 2 highest risk subgroups comprised i) children not meeting physical activity guidelines, with at least one BMI-defined obese parent and 2 abdominally obese parents, living in disadvantaged neighborhoods without parks and, ii) children with these characteristics, except with access to ≥1 park and with access to ≥1 convenience store. Group membership was strongly associated with BMI at baseline, but did not systematically predict change in BMI. CONCLUSION: Findings support the notion that obesity is predicted by multiple factors in different settings and provide some indications of potentially obesogenic environments. Alternate group definitions as well as longer duration of follow up should be investigated to predict change in obesity.

Age-dependent recombination rates in human pedigrees.

In humans, chromosome-number abnormalities have been associated with altered recombination and increased maternal age. Therefore, age-related effects on recombination are of major importance, especially in relation to the mechanisms involved in human trisomies. Here, we examine the relationship between maternal age and recombination rate in humans. We localized crossovers at high resolution by using over 600,000 markers genotyped in a panel of 69 French-Canadian pedigrees, revealing recombination events in 195 maternal meioses. Overall, we observed the general patterns of variation in fine-scale recombination rates previously reported in humans. However, we make the first observation of a significant decrease in recombination rates with advancing maternal age in humans, likely driven by chromosome-specific effects. The effect appears to be localized in the middle section of chromosomal arms and near subtelomeric regions. We postulate that, for some chromosomes, protection against non-disjunction provided by recombination becomes less efficient with advancing maternal age, which can be partly responsible for the higher rates of aneuploidy in older women. We propose a model that reconciles our findings with reported associations between maternal age and recombination in cases of trisomies.

Exploring ethnic and racial differences in intraocular pressure and glaucoma: The Canadian Longitudinal Study on aging.

Purpose: To determine whether self-reported race/ethnicity is associated with intraocular pressure (IOP) and glaucoma and to explore whether any associations are due to social, behavioral, genetic, or health differences. Design: Cross-sectional analysis of population-based data. Methods: We used the Canadian Longitudinal Study on Aging Comprehensive Cohort, which consists of 30,097 adults aged 45-85 years. Race/ethnicity was self-reported. Corneal-compensated intraocular pressure (IOP) was measured in mmHg using the Reichert Ocular Response Analyzer. Participants were asked to report if they have ever had a diagnosis of glaucoma and whether they used eye care in the past year. A glaucoma polygenic risk score (PRS) was calculated. Logistic and linear regression models were used. Results: Black individuals had higher mean IOP levels (beta coefficient (ß) = 1.46; 95% confidence interval [CI], 0.62, 2.30) while Chinese, Japanese and Korean (ß = -1.00; 95% CI, -1.63, -0.38) and Southeast Asian and Filipino individuals (ß = -1.56; 95% CI, -2.68, -0.43) had lower mean IOP levels as compared to White individuals after adjustment for sociodemographic, behavioral, genetic, and health-related variables. Black people were more likely to report glaucoma as compared to White people after adjustment (odds ratio [OR] = 2.43; 95% CI, 1.27, 4.64). Conclusion: Racial and ethnic differences in IOP and glaucoma were identified. Adjusting for sociodemographic, behavioral, genetic, and health-related variables did not fully explain these differences. Longitudinal research is needed to further explore the reasons for these differences and to understand their relevance to disease pathogenesis and progression.

Female-to-male breeding ratio in modern humans-an analysis based on historical recombinations.

Was the past genetic contribution of women and men to the current human population equal? Was polygyny (excess of breeding women) present among hominid lineages? We addressed these questions by measuring the ratio of population recombination rates between the X chromosome and the autosomes, rho(X)/rho(A). The X chromosome recombines only in female meiosis, whereas autosomes undergo crossovers in both sexes; thus, rho(X)/rho(A) reflects the female-to-male breeding ratio, beta. We estimated beta from rho(X)/rho(A) inferred from genomic diversity data and calibrated with recombination rates derived from pedigree data. For the HapMap populations, we obtained beta of 1.4 in the Yoruba from West Africa, 1.3 in Europeans, and 1.1 in East Asian samples. These values are consistent with a high prevalence of monogamy and limited polygyny in human populations. More mutations occur during male meiosis as compared to female meiosis at the rate ratio referred to as alpha. We show that at alpha not equal 1, the divergence rates and genetic diversities of the X chromosome relative to the autosomes are complex functions of both alpha and beta, making their independent estimation difficult. Because our estimator of beta does not require any knowledge of the mutation rates, our approach should allow us to dissociate the effects of alpha and beta on the genetic diversity and divergence rate ratios of the sex chromosomes to the autosomes.

Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (µ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.

The association between the Angiotensin-Converting Enzyme-2 gene and blood pressure in a cohort study of adolescents.

BACKGROUND: The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on chromosome X, is believed to be implicated in blood pressure regulation. However the few studies that have examined this association have yielded mixed results. The objective of this study was to assess the association between tag single nucleotide polymorphisms (SNPs) in the angiotensin-converting enzyme-2 gene with blood pressure and blood pressure change in adolescents. METHODS: Participants in the Nicotine Dependence in Teens (NDIT) cohort study with blood or saliva samples and at least 3 blood pressure measurements over 5 years were included in the analytic sample (n = 555). Linear growth curve models stratified on sex and ethnicity were used to assess the association between four tag SNPs in the ACE2 gene and systolic (SBP) and diastolic blood pressure (DBP), and blood pressure change. RESULTS: In males of European descent, rs2074192 and rs233575 were significantly associated with SBP and DBP, and rs2158083 was associated with SBP. In French Canadian males, rs233575 and rs2158083 were significantly associated with DBP. Among females of European descent, rs2074192, rs233575, and rs2158083 were significantly associated with change in SBP over 5 years. CONCLUSIONS: This is the first study to assess the association between the ACE2 gene with blood pressure and blood pressure change in a cohort of adolescents. Results indicate that several ACE2 gene SNPs are associated with blood pressure or blood pressure change in persons of European descent. However the therapeutic potential of these SNPs should be explored.