Marie-Hélène Roy-Gagnon

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.

Stability of the diurnal cortisol profile in children and adolescents

The diurnal cortisol profile has been implicated in multiple physical and mental health conditions in children and adolescents; however, current knowledge regarding the stability of the diurnal cortisol profile is largely based on adults. Developmental changes throughout childhood and adolescence warrant examination of the stability of the diurnal cortisol profile during this stage in the lifecourse. The aim of the present study was to conduct a comprehensive evaluation of the diurnal cortisol profile in children and adolescents. Participants (N=233; M=12.40, SD=1.83; 44.2% girls) in the Healthy Heart Project collected saliva samples, completed demographic questionnaires, and recorded bed and waking time. Intra-class correlations were calculated to evaluate the stability of aggregate and single sample measures of the diurnal cortisol profile. Total cortisol concentration (AUC(TG), AUC(AG)) and maximum sample were the most stable cortisol measures (ICC(avg)=0.54). Dynamic measures (AUC(I), slope; ICC(avg)=0.22) and other single sample measures (awake, lunch, dinner, bedtime, morning random, day random; ICC(avg)=0.28) were less stable. Of the developmentally relevant covariates tested, sleep duration, adrenarche, and time of awakening were most associated with cortisol values. Altogether, the diurnal cortisol profile yielded moderate to high stability in children and adolescents. These findings can inform methodological decisions regarding cortisol sampling protocols for children and adolescents.

Genomic and genealogical investigation of the French Canadian founder population structure.

Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness.

Rate of Endophthalmitis After Cataract Surgery in Quebec, Canada, 1996-2005

OBJECTIVE To estimate the annual incidence of endophthalmitis after cataract surgery from January 1, 1996, through December 31, 2005, in Quebec, Canada. METHODS Deidentified data were obtained from an outpatient physician billing database (Quebec State Control for Health Insurance [RAMQ]) with regard to all cataract surgical procedures performed from January 1, 1996, through December 31, 2005, in Quebec. For this cohort, records of an International Classification of Diseases, Ninth Revision (ICD-9) code for endophthalmitis during the same years were requested from 2 sources: the RAMQ outpatient database and an inpatient hospital discharge database (Maintenance and Exploitation of Data for the Study of Hospitalized Patients [MED-ECHO]). Endophthalmitis after cataract surgery was assumed if it occurred within 90 days of the surgery. Risk factors were examined using chi(2) tests and logistic regression. RESULTS After exclusions, 490 690 cataract surgical procedures were performed from January 1, 1996, through December 31, 2005. A total of 754 cases of endophthalmitis occurred within 90 days after surgery for an overall incidence rate of 1.5 per 1000 surgical procedures (95% confidence interval [CI], 1.4-1.7). Factors associated with endophthalmitis included age of 85 years or older (odds ratio [OR], 1.34; 95% CI, 1.06-1.70), male sex (1.44; 1.24-1.66), later year of surgery (0.94; 0.92-0.97), and region of cataract surgery, because regions 6 (2.21; 1.91-2.55) and 9 (4.00; 2.48-6.43) had higher rates compared with all other regions. CONCLUSION Reasons that explain the apparent decrease in endophthalmitis, especially in 2005, should be explored and further research performed to understand why certain patients and regions have higher risks of endophthalmitis after cataract surgery.

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.

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.

Cohort Profile: The Nicotine Dependence in Teens (NDIT) Study

The Nicotine Dependence in Teens (NDIT) study is a prospective cohort investigation of 1294 students recruited in 1999-2000 from all grade 7 classes in a convenience sample of 10 high schools in Montreal, Canada. Its primary objectives were to study the natural course and determinants of cigarette smoking and nicotine dependence in novice smokers. The main source of data was self-report questionnaires administered in class at school every 3 months from grade 7 to grade 11 (1999-2005), for a total of 20 survey cycles during high school education. Questionnaires were also completed after graduation from high school in 2007-08 and 2011-12 (survey cycles 21 and 22, respectively) when participants were aged 20 and 24 years on average, respectively. In addition to its primary objectives, NDIT has embedded studies on obesity, blood pressure, physical activity, team sports, sedentary behaviour, diet, genetics, alcohol use, use of illicit drugs, second-hand smoke, gambling, sleep and mental health. Results to date are described in 58 publications, 20 manuscripts in preparation, 13 MSc and PhD theses and 111 conference presentations. Access to NDIT data is open to university-appointed or affiliated investigators and to masters, doctoral and postdoctoral students, through their primary supervisor (www.nditstudy.ca).

Age-related eye disease and cognitive function.

PURPOSE To determine whether people with age-related eye disease have lower cognitive scores than people with healthy vision. METHODS A hospital-based cross-sectional study was performed in which 420 people aged 65 and older from the ophthalmology clinics at Maisonneuve-Rosemont Hospital (Montreal, Canada) were recruited who had age-related macular degeneration (AMD), Fuchs corneal dystrophy, or glaucoma. Patients with AMD and Fuchs had to have visual acuity in the better eye of worse than 20/40 while patients with glaucoma had to have visual field in their worse eye of at least -4 dB. Controls, recruited from the same clinics, did not have significant vision loss. Cognitive status was measured using the Mini-Mental State Exam Blind Version (range, 0-22) which excludes eight items that rely on vision. Linear regression with bootstrapped standard errors was used to adjust for demographic and medical factors. RESULTS People with AMD, Fuchs corneal dystrophy, and glaucoma had lower cognitive scores, on average, than controls (P < 0.05). These relationships remained statistically significant after adjusting for factors such as age, sex, race, education, living alone, systemic comorbidities, and lens opacity. CONCLUSIONS People with vision loss due to three different age-related eye diseases had lower cognitive scores. Reasons for this should be explored using longitudinal studies and a full battery of cognitive tests that do not rely on vision.

Genome-wide patterns of identity-by-descent sharing in the French Canadian founder population.

In genetics the ability to accurately describe the familial relationships among a group of individuals can be very useful. Recent statistical tools succeeded in assessing the degree of relatedness up to 6–7 generations with good power using dense genome-wide single-nucleotide polymorphism data to estimate the extent of identity-by-descent (IBD) sharing. It is therefore important to describe genome-wide patterns of IBD sharing for more remote and complex relatedness between individuals, such as that observed in a founder population like Quebec, Canada. Taking advantage of the extended genealogical records of the French Canadian founder population, we first compared different tools to identify regions of IBD in order to best describe genome-wide IBD sharing and its correlation with genealogical characteristics. Results showed that the extent of IBD sharing identified with FastIBD correlates best with relatedness measured using genealogical data. Total length of IBD sharing explained 85% of the genealogical kinship’s variance. In addition, we observed significantly higher sharing in pairs of individuals with at least one inbred ancestor compared with those without any. Furthermore, patterns of IBD sharing and average sharing were different across regional populations, consistent with the settlement history of Quebec. Our results suggest that, as expected, the complex relatedness present in founder populations is reflected in patterns of IBD sharing. Using these patterns, it is thus possible to gain insight on the types of distant relationships in a sample from a founder population like Quebec.

The heritability of glaucoma-related traits corneal hysteresis, central corneal thickness, intraocular pressure, and choroidal blood flow pulsatility.

Purpose The purpose of this work was to investigate the heritability of potential glaucoma endophenotypes. We estimated for the first time the heritability of the pulsatility of choroidal blood flow. We also sought to confirm the heritability of corneal hysteresis, central corneal thickness, and 3 ways of measuring intraocular pressure. Methods Measurements were performed on 96 first-degree relatives recruited from Maisonneuve-Rosemont Hospital in Montreal. Corneal hysteresis was determined using the Reichert Ocular Response Analyser. Central corneal thickness was measured with an ultrasound pachymeter. Three measures of intraocular pressure were obtained: Goldmann-correlated and corneal compensated intraocular pressure using the Ocular Response Analyser, and Pascal intraocular pressure using the Pascal Dynamic Contour Tonometer. The pulsatility of choroidal blood velocity and flow were measured in the sub-foveolar choroid using single-point laser Doppler flowmetry (Oculix). We estimated heritability using maximum-likelihood variance components methods implemented in the SOLAR software. Results No significant heritability was detected for the pulsatility of choroidal blood flow or velocity. The Goldman-correlated, corneal compensated, and Pascal measures of intraocular pressure measures were all significantly heritable at 0.94, 0.79, and 0.53 after age and sex adjustment (p = 0.0003, p = 0.0023, p = 0.0239). Central corneal thickness was significantly heritable at 0.68 (p = 0.0078). Corneal hysteresis was highly heritable but the estimate was at the upper boundary of 1.00 preventing us from giving a precise estimate. Conclusion Corneal hysteresis, central corneal thickness, and intraocular pressure are all heritable and may be suitable as glaucoma endophenotypes. The pulsatility of choroidal blood flow and blood velocity were not significantly heritable in this sample.