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Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIAmuscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4–23have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26application of polygenic scores in clinical practice.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P< 1 × 10−6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARBlocus for carbohydrate intake and a rare variant in DRAM1locus for protein intake, and corroborating earlier FGF21and FTOfindings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

This study examined the relationship between yogurt consumption, family history of obesity (FHO), and health determinants. Youth (n= 198; mean age: 20 ± 0.5 years) from the Québec Family Study were first classified based on their FHO, defined as the presence or absence of at least one obese (BMI ≥30 kg/m2) parent [with FHO (FHO+; n= 112) or without FHO (FHO−; n= 86)] and then on their yogurt consumption [yogurt consumers (YC+) n= 61 or non-consumers (YC−) n= 137]. A two-factor mixed ANOVA was performed to evaluate the association between FHO, YC, and their interaction with health determinant such as weight and body composition, metabolic and behavioral profiles. There was a main effect of FHO, but not YC, for weight and body composition, but no interaction between YC and FHO for these measures. However, a significant interaction between YC and FHO was observed for fasting insulin (P= 0.02), insulin area under the curve (AUC) (P= 0.02), and homeostatic model assessment of insulin resistance (HOMA-IR; P= 0.03) after adjustment for studied covariates. Specifically, lower fasting plasma insulin, insulin AUC, and HOMA-IR were observed in FHO+ and YC+ youth compared to YC− youth of the same group while no differences were found between the FHO− sub-groups. Consuming yogurt may protect against insulin resistance more specifically among youth at risk of obesity, and this relationship appears to be independent of body composition and lifestyle factors measured in this study.

ABSTRACTEpigenetic factors such as DNA methylation are DNA alterations affecting gene expression that can convey environmental information through generations. Only a few studies have demonstrated epigenetic inheritance in humans. Our objective is to quantify genetic and common environmental determinants of familial resemblances in DNA methylation levels, using a family based sample. DNA methylation was measured in 48 French Canadians from 16 families as part of the GENERATION Study. We used the Illumina HumanMethylation450 BeadChip array to measure DNA methylation levels in blood leukocytes on 485,577 CpG sites. Heritability was assessed using the variance components method implemented in the QTDT software, which partitions the variance into polygenic (G), common environmental (C), and non-shared environmental (E) effects. We computed maximal heritability, genetic heritability, and common environmental effect for all probes (12.7%, 8.2%, and 4.5%, respectively) and for statistically significant probes (81.8%, 26.9%, and 54.9%, respectively). Higher maximal heritability was observed in the Major Histocompatibility Complex region on chromosome 6. In conclusion, familial resemblances in DNA methylation levels are mainly attributable to genetic factors when considering the average across the genome, but common environmental effect plays an important role when considering statistically significant probes. Further epigenome-wide studies on larger samples combined with genome-wide genotyping studies are needed to better understand the underlying mechanisms of DNA methylation heritability.

OBJECTIVES:This article presents the first study of the economic consequences of obesity and overweight in the Canadian province of Quebec. The article examines three types of direct costs: hospitalizations, medical visits and drug consumption; and one type of indirect cost: productivity loss due to disability. METHODS:The National Population Health Survey, conducted in all Canadian provinces by Statistics Canada between 1994 and 2011, provides self-reported longitudinal data for body mass index and the frequency of health care utilization and disability. RESULTS:When we compared obese adults in Quebec to those with a normal weight at the beginning of the follow-up period, we observed that the former had significantly more frequent visits to the physician, more frequent hospital stays and higher consumption of drugs between 1994 and 2011. We estimated the annual cost of the excess health care utilization and excess disability at more than CAD $2.9 billion in 2011. CONCLUSION:The results confirm that, similar to what had been found elsewhere in Canada and abroad, there are important economic consequences associated with overweight and obesity in Quebec. OBJECTIFS:Cet article présente les résultats de la première étude sur les conséquences économiques de l’obésité et de l’embonpoint au Québec. Il examine trois types de coûts directs (hospitalisation, consultations médicales et consommation de médicaments) et un type de coût indirect (les pertes de productivité liées à l’invalidité). MÉTHODES:L’Enquête nationale sur la santé de la population, qui a été menée par Statistiques Canada dans toute les provinces canadiennes entre 1 994 et 2011, offre des données auto-rapportées longitudinales sur l’indice de masse corporelle, la fréquence d’utilisation de services de santé et l’invalidité. RÉSULTATS:Lorsqu’on compare les adultes québécois obèses avec ceux de poids normal au début de la période de suivi, nous observons que ceux-là ont consulté plus fréquemment le médecin, ont eu de plus nombreuses nuits d’hospitalisations et ont consommé plus de médicaments entre 1994 et 2011. Nous estimons le coût annuel de l’excédent d’utilisation de service de santé et d’invalidité à plus de CAD $2,9 milliards en 2011. CONCLUSION:Les résultats confirment, comme l’indiquent les études ailleurs au Canada et à l’étranger, que l’obésité et l’embonpoint sont associés à d’importantes conséquences économiques.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N= 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Cardiovascular complications (CVC) are the most common causes of death in patients with type 2 diabetes (T2D). However the pathophysiological determinants and molecular mechanisms involved in the progression of CVC in T2D are poorly understood. We have undertaken the challenging task of identifying some of the genetic and clinical determinants of CVC through a unique multidisciplinary approach involving Canadian and Finnish investigators. We are studying novel animal models combining atherosclerosis, diet-induced obesity and T2D to understand the molecular basis of CVC in obesity-linked T2D. We are also conducting clinical studies to identify key determinants of CVC in T2D patients and to determine whether a lifestyle modification program targeting loss of visceral adipose tissue/ectopic fat could be associated with clinical benefits in these patients. Together, we strongly believe that we can fill some gaps in our understanding of the CVC pathogenesis in T2D and identify novel therapeutic targets and hope that this new knowledge may be translated into the design of effective clinical interventions to optimally reduce cardiovascular risk in T2D subjects.

Objective: Dietary patterns are used to evaluate the effects of overall nutritional habits on health status, and low-density lipoprotein–peak particle diameter (LDL-PPD) has been recognized as an emerging risk factor for cardiovascular disease (CVD). The aim of this study is to verify whether an association exists between dietary patterns and LDL-PPD.Methods: A total of 635 participants aged between 18 and 55 years were included in this cross-sectional study. Nutritional information was collected with a validated food frequency questionnaire. To establish dietary patterns, factor analysis was performed, which led to characterization of the Western and Prudent dietary patterns. Nondenaturing 2%–16% polyacrylamide gradient gel electrophoresis was used to characterize LDL-PPD.Results: The Western pattern was characterized by high consumption of food such as refined grains, French fries, and red meats, and the Prudent pattern by nonhydrogenated fat, vegetables, eggs, and fish. For the Western profile, a negative correlation was found between score value and LDL-PPD before (r= −0.082, p= 0.039) and after adjustment for age (r= −0.080, p= 0.043). A negative correlation between scores for the Prudent profile and the LDL-PPD adjusted for age, sex, plasma triglycerides, and energy was observed (r= −0.12204, p= 0.0021). After division by tertiles and adjustment for the confounding effects of age, sex, plasma triglyceride levels, and energy, a significant difference (p= 0.0015) in LDL-PPD was noted between the highest tertile (255.21 ± 3.61 Å) and the lowest tertile (255.79 ± 3.68 Å) of the Prudent pattern.Conclusions: Dietary patterns, such as the Western and the Prudent, are associated with LDL-PPD. Dietary patterns can be used to assess the effects of nutritional habits on health status.

In a whole-genome scan, a single nucleotide polymorphism SNP rs7566605 upstream of the insulin-induced gene 2 INSIG2was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2variants might play a role in the regulation of plasma lipid and lipoprotein levels.

The aim of this study was to assess the effects of implementation intentions on leisure-time physical activity, taking into account the stability of intention. At baseline (T0), 349 participants completed a psychosocial questionnaire and were randomly assigned to implementation intention or control condition. Three months after baseline assessment (T1), participants in the experimental group were asked to plan where, when, and how they would exercise. Leisure-time physical activity was assessed 3 mo. later (i.e., at 6-mo. follow-up; T2). The intervention had no significant effect on physical activity at 6-mo. follow-up. However, a significant interaction of group and intention stability was observed, with the effect of the intervention on behaviour statistically significant only among those with unstable intention. Intention stability thus moderated the effect of the intervention, i.e., the intervention was more successful among individuals who needed support to change (unstable intenders).

A large body of evidence suggests that the environment plays an important role in the development of obesity. The hormone-sensitive lipase (encoded by the LIPEgene) is an intracellular enzyme that mobilises fat stores in a hormone-stimulated manner. The aim of the present study was to determine the effects of the LIPEC-60G polymorphism on body fat and plasma lipid and lipoprotein concentrations, and to test for its interaction with physical activity. The LIPEC-60G polymorphism was genotyped in 862 subjects from the Quebec Family Study. Body mass index (BMI), fat mass, percentage body fat, abdominal fat areas assessed by computed tomography, and detailed fasting plasma lipid and lipoprotein profiles were measured. Levels of physical activity were estimated using a three-day diary, and a moderate to strenuous physical activity score was retained for this study. The main effects of the LIPEC-60G polymorphism, physical activity and their interaction were determined by regression analyses separately in men and women using the MIXED model procedure. In men, we observed significant gene-physical activity interactions for BMI (p= 0.006), fat mass (p= 0.04), abdominal visceral fat area (p= 0.005) and plasma cholesterol (C) high-density lipoprotein cholesterol (HDL-C) ratio (p= 0.003). A high level of physical activity was associated with reduced adiposity and a lower plasma-C/HDL-C ratio, but only in non-carriers of the genetic variant (G-60 allele). In women, no evidence of a gene by physical activity interaction was observed, except for subcutaneous abdominal fat (p= 0.05). These results suggest that the associations between physical activity and body fat and plasma lipoprotein/lipid concentrations in men are dependent on the LIPEC-60G polymorphism, and highlight the importance of taking into account the role of gene-physical activity interactions in candidate gene studies of obesity and obesity-related traits.

Fruit and vegetable (F&V) consumption is generally associated with the prevention of major chronic diseases. For monitoring purposes, public health researchers require short but reliable and valid questionnaires to assess F&V consumption. The aim of the present study was to validate a brief one-page self-administered fruit and vegetable questionnaire (FV-Q) for obese and non-obese populations. The validation study was conducted from 2004 to 2006, among a sample of 350 obese and non-obese French-speaking participants. The six-item FV-Q was designed to measure F&V consumption over a seven-day period. It was validated against an interviewer-administered Food Frequency Questionnaire (FFQ) by means of correlation analysis and computing of epidemiologic indices. The analyses were performed separately for obese and non-obese individuals in order to account for potential different reporting patterns and the absence of such validation in obese populations. All the analyses were performed during 2007. For obese and non-obese participants, the Pearson correlation coefficients between the FV-Q and FFQ were, respectively, r = 0.66 (p<0.0001) and r = 0.65 (p<0.0001) for the mean daily intake. Values for sensitivity and specificity were 88.5% and 63.6% for obese individuals and 80.0% and 65.6% for non-obese individuals, respectively. Positive predictive values were moderate in both groups, whereas negative predictive values were very good. Overall, results were very similar for obese and non-obese individuals. This brief F&V questionnaire can be used to identify people requiring nutritional counseling. Moreover, it can be used for both obese and non-obese populations. La consommation de fruits et de légumes est généralement associée à la prévention des grandes maladies chroniques. Dans un but de surveillance, les chercheurs en santé publique ont besoin de questionnaires courts mais fiables pour déterminer cette consommation. Nous avons voulu valider le QFL, un questionnaire auto-administré d’une seule page permettant de mesurer la consommation de fruits et de légumes dans des populations obèses et non obèses. Notre étude de validation a été conduite entre 2004 et 2006 auprès de 350 participants obèses et non obèses de langue française. Le questionnaire en six points mesure la consommation de fruits et de légumes sur une période de sept jours. Il a été validé par rapport au FFQ (un questionnaire sur la fréquence de consommation des produits alimentaires administré par entrevue) au moyen d’une analyse de corrélation et d’indices épidémiologiques. Pour pallier d’éventuelles différences dans la façon de répondre au questionnaire et permettre son usage auprès d’une population obèse, les analyses ont été effectuées séparément pour les sujets obèses et non obèses. Toutes les analyses ont été effectuées pendant l’année 2007. En ce qui concerne la consommation quotidienne moyenne, les coefficients de Pearson entre le QFL et le FFQ étaient de r = 0,66 (p<0,0001) pour les participants obèses et de r = 0,65 (p<0,0001) pour les non-obèses. Les valeurs de sensibilité et de spécificité étaient, respectivement, de 88,5 % et 63,6 % pour les sujets obèses et de 80,0 % et 65,6 % pour les non-obèses. Les valeurs prédictives positives étaient modérées dans les deux groupes, tandis que les valeurs prédictives négatives étaient très bonnes. En général, les résultats étaient similaires chez les obèses et les non-obèses. Ce bref questionnaire mesurant la consommation de fruits et de légumes peut être utilisé pour identifier les personnes qui nécessitent de l’assistance nutritionnelle. De plus, il peut être utilisé autant auprès de populations obèses que non obèses.

Background: In order to evaluate the impact of severe obesity and its treatment on quality of life (QoL), it would be important to first identify the areas of QoL most likely to be affected by the disease. Methods: We first constructed a list of 187 items potentially related to QoL of patients with morbid obesity. From this list, consecutive candidates for bariatric surgery were asked to identify what they felt were the most significant items and to grade their importance. The item impact was determined from the proportion of patients who identified it as important, and the mean importance score attributed to this item (impact score = frequency X importance). Results: 100 patients (68 female; mean body mass index 51.5 kg/m2; mean age 42) were interviewed. Overall, the impact of morbid obesity was more important in women than in men. The areas of impairment were very similar in both groups, with the important difference that women ranked their dissatisfaction with physical appearance higher than men. The items having the most important impact on QoL clustered into 7 domains: 1) activity/mobility; 2) symptoms; 3) personal hygiene/clothing; 4) emotions; 5) social interactions; 6) sexual life; and 7) eating behavior. Conclusion: The impact of morbid obesity on QoL is not limited to the activity/mobility domain. Morbid obesity contributes to the impairment of all domains of what is usually referred to as "health-related quality of life".

AbstractThis paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Research Methods and Procedures: Eating behavioral traits were assessed with the Three‐Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent‐offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non‐familial environmental factors and gene‐gene and gene‐environmental interactions seem to be the major determinants of the eating/behavioral traits.

Obesity is associated with increased plasma levels of plasminogen-activator inhibitor-1 (PAI1), the major fibrinolysis inhibitor. PAI1 levels are also increased at menopause, a condition that is associated with fat mass gain, especially in the abdominal area.

This paper presents the eleventh update of the human obesity gene map, which incorporates published results up to the end of October 2004. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTLs) from animal cross‐breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2004, 173 human obesity cases due to single‐gene mutations in 10 different genes have been reported, and 49 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 166 genes which, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 221. The number of human obesity QTLs derived from genome scans continues to grow, and we have now 204 QTLs for obesity‐related phenotypes from 50 genome‐wide scans. A total of 38 genomic regions harbor QTLs replicated among two to four studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably with 358 findings of positive associations with 113 candidate genes. Among them, 18 genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, >600 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful publications and genomic and other relevant sites can be found at http:obesitygene.pbrc.edu.

The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2.

Substantial evidence exists suggesting that small, dense LDL particles are associated with an increased risk of coronary heart disease. This disease-related risk factor is recognized to be under both genetic and environmental influences. Several studies have been conducted to elucidate the genetic architecture underlying this trait, and a review of this literature seems timely. The methods and strategies used to determine its genetic component and to identify the genes have greatly changed throughout the years owing to the progress made in genetic epidemiology and the influence of the Human Genome Project. Heritability studies, complex segregation analyses, candidate gene linkage and association studies, genome-wide linkage scans, and animal models are all part of the arsenal to determine the susceptibility genes. The compilation of these studies clearly revealed the complex genetic nature of LDL particles.

A role for melanocortin signaling in the regulation of body weight in humans has been clearly established. Haploinsufficiency of the type 4 melanocortin receptor is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. Agouti-related peptide (AGRP) is an endogenous antagonist of melanocortin signaling. Therefore, loss of AGRP function could lead to the expression of a lean phenotype. We investigated the potential role of AGRP in human weight regulation by examining the association between the Ala67Thr AGRP polymorphism and indices of body composition. Significant associations were found between homozygosity for this mutation (n = 8) and body composition phenotype in 874 subjects of the Quebec family study (QFS). By PCR-RFLP analysis, we have identified eight individuals who are homozygous for the 67Thr variant allele within the QFS population, where none were observed in SAFHS. The eight QFS homozygote individuals have lower weight (−16%; P = 0.02), body mass index (−17%; P = 0.01), fat free mass (−9%; P = 0.002), fat mass (FM) (−20%; P = 0.04), and leptin (−20%; P = 0.02) when compared to those carrying at least one 67Ala allele. Individuals homozygous for the 67Thr allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the Ala67Thr AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body FM. We did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system, thus the mechanism of this effect requires further investigation. © 2004 Wiley-Liss, Inc.

This is the tenth update of the human obesity gene map, incorporating published results up to the end of October 2003 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. Transgenic and knockout murine models relevant to obesity are also incorporated (N= 55). As of October 2003, 41 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. QTLs reported from animal models currently number 183. There are 208 human QTLs for obesity phenotypes from genome‐wide scans and candidate regions in targeted studies. A total of 35 genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 272 studies reporting positive associations with 90 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. Overall, more than 430 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu.

Des progrès considérables ont été accomplis au cours des dix dernières années dans la compréhension des bases génétiques de l’obésité et des complications métaboliques qui lui sont associées. Il est maintenant bien établi que les différentes formes d’obésité constituent des états ayant tendance à se concentrer dans les familles et que les ressemblances familiales qu’on observe sont en partie déterminées par les gènes. Le nombre de gènes potentiellement impliqués dans le développement de l’obésité ne cesse de croître. Cet article fait le point sur le rôle de l’hérédité dans l’obésité et sur les gènes et locus qui ont, à ce jour, été associés à l’obésité au sein de l’étude des familles de Québec.

Objective: To determine the contribution of the peroxisome proliferator‐activated receptor α (PPARα) L162V mutation to the variation of several indexes of body fatness obtained from healthy adults who participated in the Quebec Family Study. Research Methods and Procedures: The PPARα L162V mutation was determined by a mismatch polymerase chain reaction method. Adiposity phenotypes were obtained by standardized anthropometric measurements, underwater weighing technique, and computed tomography. Results: For all adiposity phenotypes, subjects carrying the V162 allele had lower values compared with L162 homozygotes (HMZs) [BMI (kg/m2): 27.8 ± 7.6 vs. 26.0 ± 5.6, p< 0.05; percentage body fat: 28.5 ± 10.7 vs. 25.7 ± 10.1, p< 0.05; waist circumference (cm): 89.0 ± 18.1 vs. 85.7 ± 15.8, p= 0.07; total computed tomography abdominal fat areas (cm2): 406 ± 221 vs. 359 ± 192, p= 0.15; means ± SD for L162 HMZs vs. V162 carriers, respectively]. Differences in cross‐sectional abdominal adipose tissue areas and waist circumference were abolished after adjustment for total body fat mass. Similar trends were observed when results were analyzed by gender, although associations seemed stronger in women. The odds ratio of having a BMI above 30 kg/m2reached 1.77 (1.02; 3.07, 95% confidence intervals) for L162 HMZs. This risk could be considered marginal on an individual basis, but because 85% of the subjects are affected by this small risk, the impact on the population is important. Discussion: The PPARα V162 allele is associated with reduced adiposity and has a substantial population‐attributable risk.

We investigated whether the Arg16Gly and Gln27Glu polymorphisms of the β2‐adrenergic receptor gene were associated with body‐fat and fat‐distribution phenotypes measured before and in response to a 20‐week endurance‐training program. BMI, fat mass (FAT), percentage of body fat (%FAT), sum of eight skinfolds (SF8), and abdominal fat areas assessed by computed tomography were measured in adult sedentary white and black participants of the HERITAGE Family Study. Evidence of gene‐by‐obesity interaction was found in whites for several adiposity phenotypes measured before training. Analyses performed separately in nonobese and obese subjects revealed that obese men carrying the Glu27allele have lower fat accumulation (BMI, FAT, and %FAT) than noncarriers. Among white obese women, Gly16Gly homozygotes had a lower fat accumulation (BMI, FAT, and SF8) than Arg16Gly and Arg16Arg carriers. In response to endurance training, white women with the Arg16Arg genotype exhibited a greater reduction in BMI, FAT, and %FAT. Results observed in blacks were mostly negative. These results suggest that polymorphisms in the β2‐adrenergic receptor gene influence the amount of body fat in white obese men (Gln27Glu) and women (Arg16Gly), as well as the changes in adiposity in response to endurance training in white women (Arg16Gly).

This is the ninth update of the human obesity gene map, incorporating published results through October 2002 and continuing the previous format. Evidence from single‐gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) from human genome‐wide scans and various animal crossbreeding experiments, and association and linkage studies with candidate genes and other markers is reviewed. For the first time, transgenic and knockout murine models exhibiting obesity as a phenotype are incorporated (N= 38). As of October 2002, 33 Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and the causal genes or strong candidates have been identified for 23 of these syndromes. QTLs reported from animal models currently number 168; there are 68 human QTLs for obesity phenotypes from genome‐wide scans. Additionally, significant linkage peaks with candidate genes have been identified in targeted studies. Seven genomic regions harbor QTLs replicated among two to five studies. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 222 studies reporting positive associations with 71 candidate genes. Fifteen such candidate genes are supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. More than 300 genes, markers, and chromosomal regions have been associated or linked with human obesity phenotypes. The electronic version of the map with links to useful sites can be found at http:obesitygene.pbrc.edu.

A genome-wide linkage scan was performed for genes affecting submaximal exercise cardiac output (Q) and stroke volume (SV) in the sedentary state and their responses to a standardized 20-wk endurance training program. A total of 509 polymorphic markers were used, and 328 pairs of siblings from 99 white nuclear families and 102 sibling pairs from 105 black family units were available. Q and SV were measured in relative steady state during exercise at 50 W (Q50 and SV50, respectively). Baseline phenotypes were adjusted for age, sex, and body surface area (BSA), and the training responses (post-training − baseline, Δ) were adjusted for age, sex, baseline BSA, and baseline value of the phenotype. Three analytical strategies were used: a multipoint variance components linkage analysis using all the family data, and regression-based single- and multipoint linkage analyses using pairs of siblings. In whites, baseline SV50 and ΔSV50 showed promising linkages (P< 0.0023) with markers on chromosomes 14q31.1 and 10p11.2, respectively. Suggestive evidence of linkage (0.01 > P> 0.0023) for ΔSV50 and Δ Q50 was detected on chromosome 2q31.1 and for baseline SV50 and Q50 on chromosome 9q32-q33. In blacks, markers on 18q11.2 showed promising linkages with baseline Q50. Suggestive evidence of linkage was found in three regions for baseline SV50 (1p21.3, 3q13.3, 12q13.2) and one for baseline SV50 and Q50 (10p14). All these chromosomal regions include several potential candidate genes and therefore warrant further studies in the HERITAGE cohort and other studies.

RANKINEN, T., L. PÉRUSSE, R. RAURAMAA, M. A. RIVERA, B. WOLFARTH, and C. BOUCHARD. The human gene map for performance and health-related fitness phenotypes the 2001 update. Med. Sci. Sports Exerc., Vol. 34, No. 8, pp. 1219–1233, 2002. This review presents the 2001 update of the human gene map for physical performance and health-related phenotypes. It is based on scientific papers published by the end of 2001. Association studies with candidate genes, genome-wide scans with polymorphic markers, and single gene defects causing exercise intolerance to variable degrees are included. The genes and markers with evidence of association or linkage with a performance or fitness phenotype in sedentary or active people, in adaptation to acute exercise or for training-induced changes are positioned on the genetic map of all autosomes and the X chromosome. Negative studies are reviewed, but a gene or locus must be supported by at least one positive study before being inserted on the map. By the end of 2000, there were 29 loci depicted on the map. The 2001 map includes 71 loci on the autosomes and two on the X chromosome. Among these genes or markers, 24 are from prior publications on exercise intolerance and four relate to other pathologies. Finally, 13 sequence variants in mitochondrial DNA have been shown to influence relevant fitness and performance phenotypes.

Objective:Associations between preproghrelin DNA variants and obesity‐related phenotypes were studied in 3004 subjects from the Québec Family Study (QFS), the HERITAGE Family Study (HERITAGE), and the Swedish Obese Subjects (SOS) Study. Research Methods and Procedures:Body mass index (BMI), fat mass (FM) from underwater weighing, and abdominal fat from computerized tomography were measured. The ghrelin polymorphisms were identified by polymerase chain reaction. Results:Arg51Gln QFS subjects (n= 6) had lower ghrelin concentrations (p= 0.007) than Arg51Arg subjects (n= 14). White preproghrelin Met72Met subjects in HERITAGE had the lowest BMI (p= 0.020), and those in the QFS cohort had the lowest FM (p< 0.001). Met72 carrier status (Met72+) was associated with lower FM (p= 0.026) and higher insulin‐like growth factor‐1 levels (p= 0.019) among blacks. Met72Met QFS subjects had less visceral fat (p= 0.002) and a lower fasting respiratory quotient (p= 0.037). HERITAGE Met72+ white subjects also showed lower exercise respiratory quotient (p= 0.030) and higher maximal oxygen uptake (p= 0.023). Furthermore, the prevalence of Met72+ was higher (19.2%; p< 0.05) in SOS subjects whose BMI was ≤25 kg/m2than in those with BMI >25 kg/m2(14.8%). SOS Met72+ obese women had a lower (11.4%; p= 0.032) prevalence of hypertension than noncarriers (23.9%). Discussion:Arg51Gln mutation was associated with lower plasma ghrelin levels but not with obesity. The preproghrelin Met72 carrier status seems to be protective against fat accumulation and associated metabolic comorbidities.

SIMONEN, R. L., L. PÉRUSSE, T. RANKINEN, T. RICE, D. C. RAO, and C. BOUCHARD. Familial aggregation of physical activity levels in the Québec family study. Med. Sci. Sports Exerc., Vol. 34, No. 7, pp. 1137–1142, 2002.

Objective:To investigate the familial resemblance of 7‐year changes in body mass and adiposity among Canadian families. Research Methods and Procedures:The sample consisted of 655 women and 660 men from 521 families who participated in the Canada Fitness Survey in 1981 and the follow‐up Campbell's Survey in 1988. Indicators of baseline and 7‐year changes in body mass and adiposity included body mass (kilograms), body mass index (BMI; kilograms per square meter), sum of five skinfolds (SF5; millimeters), and waist circumference (WC; millimeters). The data were adjusted for the effects of age and sex, and the change scores were adjusted for baseline levels. A familial correlation model was used to determine the heritability of each phenotype using maximum likelihood techniques. Results:Significant familial resemblance was observed at baseline and for 7‐year changes in all phenotypes. At baseline, moderate heritabilities were observed [body mass: heritability coefficient (h2) = 56%; BMI, h2= 39%; SF5, h2= 41%; and WC, h2= 39%], whereas values were attenuated for each change score except for WC (Δbody mass, h2= 23%; ΔBMI, h2= 14%; ΔSF5, h2= 12%; and ΔWC, h2= 45%). Discussion:Changes in body mass and adiposity significantly aggregate within families over 7 years. However, baseline values are characterized by higher heritability levels except WC. The significant heritabilities observed for change scores suggest that lifestyle, transient environmental factors, and possibly age‐related gene effects are important determinants of changes in body mass and adiposity.

Objective:Previous studies show a wide range in the percentage of variance in leptin levels attributable to genetic factors. These studies differ markedly with respect to ethnicity, study design, and statistical methodology. Therefore, the purpose of this study was to investigate heterogeneity hypotheses across ethnic groups and by adiposity level, using the same statistical methods. Research Methods and Procedures:Samples included black vs. white (HERITAGE Family Study) and random vs. obese (Québec Family Study) individuals from 432 families (1432 individuals). Heritability for leptin, alternatively adjusted for age and sex and then for age, sex, and adiposity was estimated with the use of familial correlations. Heterogeneity in the magnitude of the familial resemblance between samples and the effect of adjusting for adiposity was explored. Results:Heritability did not vary across samples stratified by adiposity level or ethnic group or across adjustment schemes. Maximal heritability, the percentage of additive phenotypic variability due to all familial sources, was 32%. Discussion:Whereas leptin and adiposity were highly correlated within individuals, removing the effects of adiposity did not significantly alter the magnitude of the familial component for leptin. Moreover, this effect did not vary as a function of ethnicity (black vs. white) or adiposity level. Thus, no evidence for heterogeneity was detected. However, a comparison among previous studies raises questions concerning possible genetic heterogeneity in other ethnic groups in which complex interactions among leptin, adiposity, and diabetes status may be important.

The uncoupling protein 3 (UCP3) is a mitochondrial membrane transporter mainly expressed in skeletal muscle that we have shown to be associated with obesity. We have analyzed UCP3 polymorphisms, Val102Ile, Tyr210Tyr, and a new microsatellite GAIVS6 located in the sixth intron, among 276 black and 503 white subjects from the HERITAGE Family Study. Linkage and association studies were undertaken with body composition variables measured in a sedentary state (baseline) and after 20 wk of endurance training (changes). Allele and genotype frequencies were found to be significantly different between whites and blacks. Suggestive linkages (0.009 ≤ P≤ 0.033) with Tyr210Tyr were found in blacks and whites for baseline body mass index, fat mass, or leptin level and with GAIVS6 in whites for changes in fat mass and percent body fat. Associations were also found in whites between GAIVS6 and changes in the sum of eight skinfold thicknesses (P= 0.0006), with a borderline result for body mass index (P= 0.06). We concluded that UCP3 could be involved in body composition changes after regular exercise.

This report constitutes the eighth update of the human obesity gene map, incorporating published results up to the end of October 2001. Evidence from the rodent and human obesity cases caused by single‐gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTLs) uncovered in human genome‐wide scans and in crossbreeding experiments in various animal models, association and linkage studies with candidate genes and other markers is reviewed. The human cases of obesity related in some way to single‐gene mutations in six different genes are incorporated. Twenty‐five Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models currently reaches 165. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 174 studies reporting positive associations with 58 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity‐related phenotypes can be found on all chromosomes except chromosome Y. A total of 54 new loci have been added to the map in the past 12 months, and the number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes is now above 250. Likewise, the number of negative studies, which are only partially reviewed here, is also on the rise.

Background: Among adrenergic receptor subtypes that regulate lipid mobilization, the α2-adrenergic receptor is involved in the inhibition of fatty acid mobilization from adipose tissue. A C-1291G polymorphism is located in the α2-adrenergic receptor gene (ADRA2A) but no association with body fat accumulation has been reported yet. Materials and Methods: Body mass index (BMI), fat mass (FAT), percentage body fat (%FAT), trunk-to-extremity skinfold ratio (TER), sum of eight skinfolds (SF8), and abdominal subcutaneous (ASF), visceral (AVF), and total (ATF) fat areas assessed by CT scan have been measured in adult sedentary white (n= 503) and black (n= 276) subjects participating in the HERITAGE Family Study. Association between the C-1291G polymorphism and each phenotype was tested separately in men and women of each race using ANCOVA with the effects of age as covariate in addition to the effects of BMI for TER and of FAT for AVF, ASF, and ATF. Results: The allele frequencies of the ADRA2A C-1291G polymorphism differed between races. No association was observed in white subjects, except for a moderate effect of the polymorphism accounting for less than 1% of the variance in AVF and ATF in women. In black subjects, however, the G-1291 allele was found to be associated with an increase of TER in men (3.8% of variance accounted for by the polymorphism), while in black women it was associated with a decrease in TER (2.9%) and in AVF (2.5%). Conclusion: These results suggest a role for the ADRA2A gene in determining the propensity to store fat in the abdominal area, independently of total body fatness.

We examined the possible association between a transforming growth factor (TGF)-β1gene polymorphism in codon 10 and blood pressure (BP) at rest, in acute response to exercise in the pretrained (sedentary) and trained states, as well as in its training response (Δ) to 20 wk of endurance exercise. Subjects were 257 black and 480 white, healthy sedentary normotensive subjects from the HERITAGE Family Study. The polymorphism was detected by polymerase chain reaction and digestion with the Msp A1 I endonuclease yielding a wild (leucine-10) and a mutant (proline-10) allele. Resting and exercise [50 W plus 60, 80, and 100% maximal oxygen consumption (V˙o2 max)] BP were determined before and after training. Significant (P< 0.05) race-genotype interactions were found for systolic (S) BP in both the sedentary and trained states. Among whites but not in blacks, the TGF-β1genotypes were significantly (P< 0.05) associated with sedentary-state SBP at rest, at 50 W, and at 60 and 100% V˙o2 maxas well as with trained-state SBP at rest and at 80 and 100%V˙o2 max. The leucine-10 homozygotes had significantly (P< 0.05) lower SBP than proline-10 homozygotes. ΔBP was not significantly associated with genotype. These results support the hypothesis of an association between the TGF-β1marker in codon 10 and SBP at rest and in response to acute exercise in whites but not in blacks.

Familial risk ratios for high blood pressure were estimated in a representative sample of the Canadian population. The sample consisted of 14,069 participants 7–69 years of age from 5,753 families participating in the 1981 Canada Fitness Survey. Resting systolic (SBP) and diastolic (DBP) blood pressures were adjusted for the effects of body mass index using regression procedures. Varying degrees of high blood pressure were defined as the 75th, 85th, and 95thpercentiles of age‐ and sex‐specific values. Age‐ and sex‐standardized risk ratios (SRRs) were calculated comparing the prevalences in the general population to those in spouses and first‐degree relatives of probands with high blood pressure. SRRs for the 95thpercentile were, for SBP and DBP, respectively, 1.37 and 1.45 in spouses and 1.33 and 2.36 in first‐degree relatives of probands. SRRs decrease with decreasing percentile cut‐offs used to define high blood pressure (95th> 85th> 75th), and SRRs are generally higher in first‐degree relatives than in spouses, particularly for DBP. The results indicate significant familial risk for high blood pressure in the Canadian population, and the pattern of SRRs suggests that genetic factors may be responsible for a portion of the risk. Am. J. Hum. Biol. 13:620–625, 2001. © 2001 Wiley‐Liss, Inc.

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index (P= 0.01), fat mass (P = 0.01), and percent body fat (P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat (P= 0.05) and a greater increase in post-heparin LPL activity (P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.

Objective:The stability of several indicators of body composition and adipose tissue distribution over 12 years was quantified. Research Methods and Procedures:The participants were 77 boys and 76 girls who were evaluated along with their parents at baseline as children and adolescents (8 to 18 years of age) and remeasured as young adults 12 years later. Indicators of body composition included the body mass index, fat mass, fat free mass, percentage of body fat, sum of six skinfolds (SF6), and the first principal component of six age‐adjusted skinfold residuals. Relative adipose tissue distribution was represented by the second principal component of skinfold residuals and a trunk‐to‐extremity skinfold ratio, adjusted for SF6. Results:Partial interage correlations, controlling for initial age and length of follow‐up, were 0.65 and 0.59 for the body mass index, 0.59 and 0.64 for fat mass, 0.65 and 0.57 for fat free mass, 0.50 and 0.57 for percentage of body fat, 0.66 and 0.44 for SF6, 0.64 and 0.42 for the first principal component of six age‐adjusted skinfold residuals, 0.19 and 0.31 for the second principal component of skinfold residuals, and 0.41 and 0.47 for trunk‐to‐extremity skinfold ratio, adjusted for SF6, in men and women, respectively. Multiple regression analyses indicated that the significant partial R2values of parental measurements on the prediction of their offspring in young adulthood ranged from 2% to 9%. Discussion:The results indicate moderately high stability of indicators of body composition and somewhat lower stability of measures of adipose tissue distribution. Overall, parental measures offer less predictive value than do measures of childhood and adolescent body composition and adipose tissue distribution.

Background: UCP3 is a mitochondrial membrane transporter that is postulated to uncouple oxidative phosphorylation from ATP synthesis producing heat instead of ATP. Human UCP3 is mainly expressed in skeletal muscle, which plays an important role in energy homeostasis and substrate oxidation. Therefore, UCP3 is a good candidate gene for obesity. Materials and Methods: We analyzed, among 734 subjects from the Québec Family Study, a new GA repeat microsatellite located in intervening sequence (IVS) 6 (GAIVS6) in UCP3 gene, and two already described restriction fragment length polymorphisms (RFLP) Y210Y(C→T) and V102I (G→A). Covariance analysis across genotypes for different adiposity, resting energy expenditure, and glucose metabolism variables was undertaken with age and sex, plus body fat and body mass for nonadiposity phenotypes, as covariates. Results: We found strong associations between GAIVS6 and body mass index (p= 0.0001), fat mass (p= 0.0005), percentage body fat (p= 0.0004), the sum of six skinfold thickness (p= 0.0001), and leptin level (p= 0.0001). Homozygote for the GAIVS6 240 bp alleles (15% frequency in QFS) showed higher adiposity than subjects with the GAIVS6 238 bp allele (70% in QFS). The exons, the 5′ untranslated region (UTR), and the exon-intron junctions of UCP3 gene from subjects homozygote for either GAIVS6 238 bp or 240 bp alleles were sequenced in search for mutations. Variants 5′UTR-55C→T and Y210Y(C→T) were detected, whereas IVS4-36C→T was uncovered, but no new exonic or splice junction mutation was observed. RFLP Y210Y(C→T) was not associated to adiposity in QFS; V102I(G→A) showed no variation. Conclusion: Our results suggest that some alleles of UCP3 are involved in the etiology of human obesity.

The human gene map for performance and health-related fitness phenotypes. Med. Sci. Sports Exerc., Vol. 33, No. 6, 2001, pp. 855–867. The aim of this paper is to describe the first human gene map for physical performance and health-related fitness traits based on the papers published until the end of 2000. Studies of candidate genes using case-control and other designs are reviewed. Quantitative trait loci from the limited evidence reported to date in genomic scans are also incorporated. Performance and fitness phenotypes in the sedentary state as well as their changes during exercise, if applicable, or in response to exercise training are considered. Physical performance traits include cardiorespiratory endurance indicators and muscular strength or muscular performance variables. Health-related fitness phenotypes are grouped under the following categories hemodynamic traits; anthropometry and body composition; insulin and glucose metabolism; and lipids, lipoproteins, and hemostatic factors. A yearly update of this human gene map will be published.