Application of the regression of offspring on mid-parent method to detect associations between single-nucleotide polymorphisms and the beta 2 electroencephalogram phenotype in the COGA data

The beta 2 electroencephalogram (EEG) phenotype is used as a quantitative measure related to alcoholism, and evidence of linkage and association has previously been reported in the Collaborative Study on the Genetics of Alcoholism data. In this study, associations between the beta 2 EEG phenotype and single nucleotide polymorphisms from whole-genome Illumina and Affymetrix panels were investigated with the regression of offspring on mid-parent method to identify significant genetic effects and to estimate their heritability. Separate regressions on father and mother were performed to identify parent-specific effects. Estimates of the heritability of the beta 2 EEG phenotype were 0.68 ± 0.12 and 0.52 ± 0.07 based on father-offspring and mother-offspring pairs, respectively. Significant associations at the 0.0005 level, some of which were parent-specific, were found on chromosomes 1, 2, 5, 6, 7, 8, 11, 12, 15, 16, 17, 18, and 19 with heritability attributable to each SNP ranging from 0.01 to 8%

When genetics and genealogies tell different stories-maternal lineages in Gaspesia

Data from uniparentally inherited genetic systems were used to trace evolution of human populations. Reconstruction of the past primarily relies on variation in present-day populations, limiting historical inference to lineages that are found among living subjects. Our analysis of four population groups in the Gaspé Peninsula, demonstrates how this may occasionally lead to erroneous interpretations. Mitochondrial DNA analysis of Gaspesians revealed an important admixture with Native Americans. The most likely scenario links this admixture to French-Canadians from the St. Lawrence Valley who moved to Gaspesia in the 19th century. However, in contrast to genetic data, analysis of genealogical record shows that Native American maternal lineages were brought to Gaspesia in the 18th century by Acadians who settled on the south-western coast of the peninsula. Intriguingly, within three generations, virtually all Métis Acadian families separated from their nonadmixed relatives and moved eastward mixing in with other Gaspesian groups, in which Native American maternal lines are present in relatively high frequencies. Over time, the carriers of these lines eventually lost memory of their mixed Amerindian-Acadian origin. Our results show that a reliable reconstruction of population history requires cross-verification of different data sources for consistency, thus favouring multidisciplinary approaches

Admixed ancestry and stratification of Quebec regional populations

Population stratification results from unequal, nonrandom genetic contribution of ancestors and should be reflected in the underlying genealogies. In Quebec, the distribution of Mendelian diseases points to local founder effects suggesting stratification of the contemporary French Canadian gene pool. Here we characterize the population structure through the analysis of the genetic contribution of 7,798 immigrant founders identified in the genealogies of 2,221 subjects partitioned in eight regions. In all but one region, about 90% of gene pools were contributed by early French founders. In the eastern region where this contribution was 76%, we observed higher contributions of Acadians, British and American Loyalists. To detect population stratification from genealogical data, we propose an approach based on principal component analysis (PCA) of immigrant founders' genetic contributions. This analysis was compared with a multidimensional scaling of pairwise kinship coefficients. Both methods showed evidence of a distinct identity of the northeastern and eastern regions and stratification of the regional populations correlated with geographical location along the St-Lawrence River. In addition, we observed a West-East decreasing gradient of diversity. Analysis of PC-correlated founders illustrates the differential impact of early versus latter founders consistent with specific regional genetic patterns. These results highlight the importance of considering the geographic origin of samples in the design of genetic epidemiology studies conducted in Quebec. Moreover, our results demonstrate that the study of deep ascending genealogies can accurately reveal population structure

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

International audienceFew 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). 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. 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. 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

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

Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents

Background: While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes. Methods: In a prospective study of 1294 adolescents aged 12–13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7–8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator). Results: The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value ,0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and selfmedication phenotypes were both 0.076. Conclusions: Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3). Impact: Dopaminergic pathways may be salient during early smoking and the development of ND

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

Correspondence between genomic- and genealogical/coalescent-based inference of homozygosity by descent in large French-Canadian genealogies

Research on the genetics of complex traits overwhelmingly focuses on the additive effects of genes. Yet, animal studies have shown that non-additive effects, in particular homozygosity effects, can shape complex traits. Recent investigations in human studies found some significant homozygosity effects. However, most human populations display restricted ranges of homozygosity by descent (HBD), making the identification of homozygosity effects challenging. Founder populations give rise to higher HBD levels. When deep genealogical data are available in a founder population, it is possible to gain information on the time to the most recent common ancestor (MRCA) from whom a chromosomal segment has been transmitted to both parents of an individual and in turn to that individual. This information on the time to MRCA can be combined with the time to MRCA inferred from coalescent models of gene genealogies. HBD can also be estimated from genomic data. The extent to which the genomic HBD measures correspond to the genealogical/coalescent measures has not been documented in founder populations with extensive genealogical data. In this study, we used simulations to relate genomic and genealogical/coalescent HBD measures. We based our simulations on genealogical data from two ongoing studies from the French-Canadian founder population displaying different levels of inbreeding. We simulated single-nucleotide polymorphisms (SNPs) in a 1-Mb genomic segment from a coalescent model in conjunction with the observed genealogical data. We compared genealogical/coalescent HBD to two genomic methods of HBD estimation based on hidden Markov models (HMMs). We found that genomic estimates of HBD correlated well with genealogical/coalescent HBD measures in both study genealogies. We described generation time to coalescence in terms of genomic HBD estimates and found a large variability in generation time captured by genomic HBD when considering each SNP. However, SNPs in longer segments were more likely to capture recent time to coalescence, as expected. Our study suggests that estimating the coalescent gene genealogy from the genomic data to use in conjunction with observed genealogical data could provide valuable information on HBD

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

Investigating Gene–Gene and Gene–Environment Interactions in the Association Between Overnutrition and Obesity-Related Phenotypes

Introduction: Animal studies suggested that NFKB1, IKBKB, and SOCS3 genes could be involved in the association between overnutrition and obesity. This study aims to investigate interactions involving these genes and macronutrient intakes affecting obesity-related phenotypes.Methods: We used a traditional statistical method, logistic regression, and compared it to alternative statistical method, multifactor dimensionality reduction (MDR) and penalized logistic regression (PLR), to better detect genes/environment interactions in the Toronto Nutrigenomics and Health Study (n = 1639) using dichotomized body mass index (BMI) and waist circumference as obesity-related phenotypes. Exposure variables included genotype on 54 single nucleotide polymorphisms (NFKB1: 18, IKBKB: 9, SOCS3: 27), macronutrient (carbohydrates, protein, fat) and alcohol intakes and ethno-cultural background.Results: After correction for multiple testing, no interaction was found using logistic regression. MDR identified interactions between SOCS3 rs6501199 and rs4969172, and IKBKB rs3747811 affecting BMI in the Caucasian population; SOCS3 rs6501199 and NFKB1 rs1609798 affecting WC in the Caucasian population; and SOCS3 rs4436839 and IKBKB rs3747811 affecting WC in the South Asian population. PLR found a main effect of SOCS3 rs12944581 on BMI among the South Asian population.Conclusion: While MDR and PLR had discordant results, some models support results from previous studies. These results emphasize the need to use alternative statistical methods to investigate high-order interactions and suggest that variants in the nutrient-responsive hypothalamic IKKB/NF-kB signaling pathway may be involved in obesity pathogenesis