New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

Etude de la composante génétique de caractères complexes dans une population isolée

My thesis project is concerned with tapping the potential of population isolates for the dissection of complex trait architecture. Specifically, isolates can aid the identification of variants that are usually rare in other populations. This thesis principally contains in depth investigations into genetic imputation and heritability analysis in isolates. We approached both of these studies from two main angles; first from a methodological standpoint where we created extensive simulation datasets in order to investigate how the specificities of an isolate should determine strategies for analyses. Secondly, we demonstrated such concepts through analysis of genetic data in the known isolate of Cilento. Imputation is a crucial step to performing association analyses in an isolate and represents a cost-efficient method for gaining dense genetic data for the population. The effectiveness of imputation is of course dependent on its accuracy. Hence, we investigated the wide range of possible strategies to gain maximal imputation accuracy in an isolate. We showed that software using algorithms which specifically evoke known characteristics of isolates were, unexpectedly, not as successful as those designed for general populations. We also demonstrated a very small study specific imputation reference panel performing very strongly in an isolate; particularly for rare variants. For many complex traits, there exist discordances between estimates of heritabilities from studies in closely related individuals and from studies on unrelated individuals. In particular, we noted that most researchers consider dominant (non-additive) genetic effects as unlikely to play a significant role despite contrasting results from previous studies on isolates. Our second analysis revealed possible mechanisms to explain such disparate published heritability estimates between isolated populations and general populations. This allowed us to make interesting deductions from our own heritability analyses of the Cilento dataset, including an indication of a non-null dominance component involved in the distribution of low-density lipoprotein level measurements (LDL). This led us to perform genome-wide association analyses of additive and non-additive components for LDL in Cilento and we were able to identify genes that had been previously linked to the trait in other studies. In the contexts of both of our studies, we observed the importance of retaining genotype uncertainty (genotype dosage following imputation or genotype likelihoods from sequencing data). As a prospective of this thesis, we have proposed ways to incorporate this uncertainty into certain methods used in this project. Our findings for imputation strategies and heritability analysis will be highly valuable for the continued study of the isolate of Cilento but will also be instructive to researchers working on other isolated populations and also applicable to the study of complex diseases in general.Mon projet de thèse vise à exploiter le potentiel des isolats de population pour étudier la composante génétique des maladies multifactorielles. En effet, les isolats peuvent faciliter l'identification des facteurs génétiques habituellement trop rares en population générale. Cette thèse est composée de deux études principalement : l'imputation génétique et l'analyse de l'héritabilité. Chacune de ces études ont été abordée sous deux angles : l’un théorique, s’appuyant sur une vaste étude de simulations basée sur les caractéristiques de la population isolée du Cilento, permettant d’évaluer des stratégies d’analyse et de déterminer la plus adéquate ; l’autre appliqué, s’appuyant sur l’analyse de données génétiques réelles issues de la même population.L'imputation génétique est une étape cruciale pour effectuer des analyses d'association dans un isolat et représente une méthode peu couteuse pour obtenir les séquences complètes du génome ou de l’exome des individus de la population. L'efficacité de cette approche dépend de la précision de l’imputation ; nous avons donc étudié plusieurs stratégies pour obtenir une précision d'imputation maximale dans un isolat. Nous avons montré que les logiciels utilisant des algorithmes qui s’appuient sur les caractéristiques particulières des isolats n’étaient pas, de façon inattendue, aussi performants que ceux conçus pour les populations générales. De plus, malgré la disponibilité de panels de référence publics contenant plusieurs milliers de chromosomes, nous avons confirmé qu’un panel de référence spécifique de la population d’étude, même de taille très réduite, était essentiel pour la qualité de l’imputation. Ceci était d’autant plus vrai pour les variantes rares.Pour de nombreux traits, il existe des discordances entre les estimations de l'héritabilité obtenues à partir d’individus apparentés et à partir d’individus non apparentés. En particulier, la plupart des chercheurs considère que les effets dominants (non additifs) ne jouent pas un rôle majeur malgré les résultats contrastés des études sur les isolats. Notre deuxième analyse a révélé des mécanismes possibles pour expliquer la disparité de ces estimations publiées entre populations isolées et populations générales. Cela nous a permis de faire des déductions intéressantes pour nos propres analyses dans le Cilento. En particulier, nous avons identifié la possibilité d'une composante de dominance non nulle pour les niveaux de lipoprotéines de basse densité (LDL). Cela nous a amenés à effectuer des analyses d'association pan-génomique des composantes additives et non-additives pour LDL dans le Cilento et nous avons pu identifier des gènes qui avaient déjà été liés au trait dans d'autres études.Dans le contexte de nos deux études, nous avons observé l'importance de conserver l'incertitude génotypique (dosage pour l’imputation, vraisemblance des génotypes pour les données de séquençage). Dans la perspective de cette thèse, nous avons proposé des moyens d’incorporer cette incertitude à certaines méthodes utilisées dans ce projet.Nos résultats concernant les stratégies d'imputation et l'analyse de l'héritabilité seront très utiles pour la poursuite de l'étude de l'isolat de Cilento. Mais, ils seront également instructifs pour les chercheurs travaillant sur d'autres populations isolées et également applicables plus généralement à l'étude des maladies complexes

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium

International audienceIncidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

International audienceAbstract Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified