The Human Obesity Gene Map: The 2003 Update

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 .     

The Human Obesity Gene Map: The 2002 Update

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 .     

The human obesity gene map: the 2005 update

This 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.     

The Human Obesity Gene Map: The 2000 Update

This report constitutes the seventh update of the human obesity gene map incorporating published results up to the end of October 2000. Evidence from the rodent and human obesity cases caused by single‐gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci uncovered in human genome‐wide scans and in cross‐breeding experiments in various animal models, and association and linkage studies with candidate genes and other markers are reviewed. Forty‐seven human cases of obesity caused by single‐gene mutations in six different genes have been reported in the literature to date. Twenty‐four Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different quantitative trait loci reported from animal models currently reaches 115. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 130 studies reporting positive associations with 48 candidate genes. Finally, 59 loci have been linked to obesity indicators in genomic scans and other linkage study designs. The obesity gene map 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.     

The Human Obesity Gene Map: The 2001 Update

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.     

The Human Obesity Gene Map: The 1999 Update

This report constitutes the sixth update of the human obesity gene map incorporating published results up to the end of October 1999. Evidence from the rodent and human obesity cases caused by single gene mutations, Mendelian disorders exhibiting obesity as a clinical feature, quantitative trait loci (QTL) uncovered in human genome‐wide scans and in crossbreeding experiments with mouse, rat, pig and chicken models, association and linkage studies with candidate genes and other markers is reviewed. Twenty‐five human cases of obesity can now be explained by variation in five genes. Twenty Mendelian disorders exhibiting obesity as one of their clinical manifestations have now been mapped. The number of different QTLs reported from animal models reaches now 98. Attempts to relate DNA sequence variation in specific genes to obesity phenotypes continue to grow, with 89 reports of positive associations pertaining to 40 candidate genes. Finally, 44 loci have 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 autosomes, with chromosomes 14 and 21 showing each one locus only. The number of genes, markers, and chromosomal regions that have been associated or linked with human obesity phenotypes continues to increase and is now well above 200.

Figure 1 Open in figure viewer PowerPoint The 1999 human obesity gene map. The map includes all putative obesity‐related phenotypes identified from the various lines of evidence reviewed in the article. The chromosomes and their regions are from the Gene Map of the Human Genome web site hosted by the National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD (URL: http:www.ncbi.nlm.nih.gov ). The chromosome number and the size of each chromosome in megabases (Mb) are given at the top and bottom of the chromosomes, respectively. Loci abbreviations and full names are given in the Appendix. The abbreviations for QTLs are given in Table 4 .     

The Human Obesity Gene Map: The 1998 Update

PÉRUSSE, LOUIS, YVON C. CHAGNON, JOHN WEISNAGEL, AND CLAUDE BOUCHARD. The human obesity gene map: the 1998 update. Obes Res. 1999;7:111–129. An update of the human obesity gene map incorporating published results up to the end of October 1998 is presented. Evidence from the human obesity cases caused by single gene mutations; other Mendelian disorders exhibiting obesity as a clinical feature; quantitative trait loci uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, and pig models; association and case-control studies with candidate genes; and linkage studies with genes and other markers is reviewed. The most noticeable changes from the 1997 update is the number of obesity cases due to single gene mutations that increased from three cases due to mutations in two genes to 25 cases due to 12 mutations in seven genes. A look at the obesity gene map depicted in Figure 1 reveals that putative loci affecting obesity-related phenotypes are found on all but chromosome Y of the human chromosomes. Some chromosomes show at least three putative loci related to obesity on both arms (1, 2, 3, 6, 7, 8, 9, 11, 17, 19, 20, and X) and several on one chromosome arm only (4q, 5q, 10q, 12q, 13q, 15q, 16p, and 22q). The number of genes and other markers that have been associated or linked with human obesity phenotypes is increasing very rapidly and now approaches 27.     

The Human Obesity Gene Map: The 1997 Update

An update of the human obesity gene map incorporating published results up to October 1997 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature; single-gene mutation rodent models; quantitative trait loci uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, and pig models; association and case-control studies with candidate genes; and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all of these loci reveals that all but chromosome Y of the 24 human chromosomes are represented. Some chromosomes show at least three putative loci related to obesity on both arms (1, 2, 6, 8, 11, and 20) and several on one chromosome arm only (3p, 4q, 5q, 7q, 12q, 13q, 15q, 15p, 22q, and Xq). Studies reporting negative association and linkage results are also listed, with the exception of the unlinked markers from genome-wide scans.     

The Human Obesity Gene Map: The 1996 Update

An update of the human obesity gene map up to October 1996 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature, single-gene mutation rodent models, quantitative trait loci uncovered in crossbreeding experiments with mouse, rat, and pig models, association and case-control studies with candidate genes, and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all these loci reveals that only 4 of the 24 human chromosomes are not yet represented, i.e., 9, 18, 21, and Y. Several chromosome arms are characterized by the presence of several putative loci. The following arms include at least three such loci: 1p, 1q, 3p, 4q, 6p, 7q, 8p, 8q, 11p, 11q, 15q, 20q, and Xq. Studies with negative association and linkage results are also reviewed.     

Large-scale in silico mapping of complex quantitative traits in inbred mice

Understanding the genetic basis of common disease and disease-related quantitative traits will aid in the development of diagnostics and therapeutics. The processs of gene discovery can be sped up by rapid and effective integration of well-defined mouse genome and phenome data resources. We describe here an in silico gene-discovery strategy through genome-wide association (GWA) scans in inbred mice with a wide range of genetic variation. We identified 937 quantitative trait loci (QTLs) from a survey of 173 mouse phenotypes, which include models of human disease (atherosclerosis, cardiovascular disease, cancer and obesity) as well as behavioral, hematological, immunological, metabolic, and neurological traits. 67% of QTLs were refined into genomic regions <0.5 Mb with approximately 40-fold increase in mapping precision as compared with classical linkage analysis. This makes for more efficient identification of the genes that underlie disease. We have identified two QTL genes, Adam12 and Cdh2, as causal genetic variants for atherogenic diet-induced obesity. Our findings demonstrate that GWA analysis in mice has the potential to resolve multiple tightly linked QTLs and achieve single-gene resolution. These high-resolution QTL data can serve as a primary resource for positional cloning and gene identification in the research community.     

Current Status of the Human Obesity Gene Map

An overview of the status of the human obesity gene map up to October 1995 is presented. The evidence is drawn from several lines of clinical and experimental research. First, 12 loci linked to Mendelian disorders exhibiting obesity as one clinical feature are reviewed. Second, six loci causing obesity in rodent models of the disease are considered. Third, eight chromosomal regions where quantitative trait loci, identified by crossbreeding experiments with informative strains of mice, are defined. Fourth, 10 candidate genes exhibiting a statistical association with BMI or body fat are introduced. Fifth, nine loci found to be linked to a relevant phenotype are listed and the four cases for which the evidence for linkage is strongest are emphasized. The latter are mapped to 2p25, 6p21.3, 7q33 and 20q12-13.11. Finally, the studies that have concluded that there was no association or linkage with a marker or gene are also reviewed. It is recommended that a system be developed by the obesity research community to ensure that an accurate and easily accessible computerized version of the human obesity gene map becomes available in the near future.     

Investigation of Obesity Candidate Genes On Porcine Fat Deposition Quantitative Trait Loci Regions

Objectives: To investigate possible obesity candidate genes in regions of porcine quantitative trait loci (QTL) for fat deposition and obesity‐related phenotypes. Research Methods and Procedures: Chromosome mapping and QTL analyses of obesity candidate genes were performed using DNA panels from a reference pig family. Statistical association analyses of these genes were performed for fat deposition phenotypes in several other commercial pig populations. Results: Eight candidate genes were mapped to QTL regions of pig chromosomes in this study. These candidate genes also served as anchor loci to determine homologous human chromosomal locations of pig fat deposition QTL. Preliminary analyses of relationships among polymorphisms of individual candidate genes and a variety of phenotypic measurements in a large number of pigs were performed. On the basis of available data, gene‐gene interactions were also studied. Discussion: Comparative analysis of obesity‐related genes in the pig is not only important for development of marker‐assisted selection on growth and fat deposition traits in the pig but also provides for an understanding of their genetic roles in the development of human obesity.     

Treatment- and population-dependent activity patterns of behavioral and expression QTLs

Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population. We introduce the concept of QTL activity patterns to characterize how associations between genomic loci and traits vary across treatments. We identified several significant behavioral QTLs and many expression QTLs (eQTLs). The behavioral QTLs are highly dependent on treatment and population. We classified eQTLs into three groups: cis-eQTLs (expression variation that maps to within 5 Mb of the cognate gene), syntenic trans-eQTLs (the gene and the QTL are on the same chromosome but not within 5 Mb), and non-syntenic trans-eQTLs (the gene and the QTL are on different chromosomes). We found that most non-syntenic trans-eQTLs were treatment-specific whereas both classes of syntenic eQTLs were more conserved across treatments. We also found there was a correlation between regions along the genome enriched for eQTLs and SNPs that were conserved across the LXS and BXD families. Genes with eQTLs that co-localized with the behavioral QTLs and displayed similar QTL activity patterns were identified as potential candidate genes associated with the phenotypes, yielding identification of novel genes as well as genes that have been previously associated with responses to ethanol.     

Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms

A systematic study has been conducted of all available reports in PubMed and OMIM (Online Mendelian Inheritance in Man) to examine the genetic and molecular basis of quantitative genetic loci (QTL) of diabetes with the main focus on genes and polymorphisms. The major question is, What can the QTL tell us? Specifically, we want to know whether those genome regions differ from other regions in terms of genes relevant to diabetes. Which genes are within those QTL regions, and, among them, which genes have already been linked to diabetes? whether more polymorphisms have been associated with diabetes in the QTL regions than in the non-QTL regions.Our search revealed a total of 9038 genes from 26 type 1 diabetes QTL, which cover 667,096,006 bp of the mouse genomic sequence. On one hand, a large number of candidate genes are in each of these QTL; on the other hand, we found that some obvious candidate genes of QTL have not yet been investigated. Thus, the comprehensive search of candidate genes for known QTL may provide unexpected benefit for identifying QTL genes for diabetes. Key Words: Quantitative trait loci, type 1 diabetes, insulin-dependent diabetes mellitus (IDDM), candidate gene, polymorphism, mouse.     

Screening of duplicated loci reveals hidden divergence patterns in a complex salmonid genome

A whole‐genome duplication (WGD) doubles the entire genomic content of a species and is thought to have catalysed adaptive radiation in some polyploid‐origin lineages. However, little is known about general consequences of a WGD because gene duplicates (i.e., paralogs) are commonly filtered in genomic studies; such filtering may remove substantial portions of the genome in data sets from polyploid‐origin species. We demonstrate a new method that enables genome‐wide scans for signatures of selection at both nonduplicated and duplicated loci by taking locus‐specific copy number into account. We apply this method to RAD sequence data from different ecotypes of a polyploid‐origin salmonid (Oncorhynchus nerka) and reveal signatures of divergent selection that would have been missed if duplicated loci were filtered. We also find conserved signatures of elevated divergence at pairs of homeologous chromosomes with residual tetrasomic inheritance, suggesting that joint evolution of some nondiverged gene duplicates may affect the adaptive potential of these genes. These findings illustrate that including duplicated loci in genomic analyses enables novel insights into the evolutionary consequences of WGDs and local segmental gene duplications.     

Genetics of Obesity: What have we Learned?

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.     

Diversification in flowering time due to tandem FT-like gene duplication, generating novel Mendelian factors in wild and cultivated rice

The complex structure of a single Mendelian factor widespread in the Asian cultivated rice ( Oryza sativa ) and its wild progenitor ( Oryza rufipogon ) that caused diverse phenotypes in the timing of flowering under natural field conditions was investigated in near isogenic lines. These near isogenic lines showed differences in flowering time despite all eight accessions collected from tropical regions possessing a recessive gene allelic to the se-pat gene. Fine mapping in two of these near-isogenic lines revealed that cultivated (Patpaku) and wild (W593) accessions had three and two linked quantitative trait loci (QTL) in the candidate regions, respectively, showing that Patpaku and W593 possessed linked QTLs with different effects in addition to the commonly-observed recessive gene ( se-pat ). Molecular dissection suggested that the tandemly duplicated FT-like genes ( Hd3a and RFT1 ) could be the candidate genes for these QTLs. Interestingly, the linked QTLs differed in their epistases, degree of dominance, and genotype × environment interactions. The nucleotide sequences showed that RFT1 has diverged more rapidly than Hd3a during rice evolution, suggesting phenotypic diversification of the two genes. Phylogenetic analysis implied that the se-pat ⁺ alleles might have emerged in different lineages within O. sativa . The present results strongly suggest that nucleotide divergence and shuffling of the linked QTLs by recombination might have created novel Mendelian factors that probably contribute to responding to local environments.     

Towards the cloning of genes underlying murine QTLs

Many quantitative trait loci (QTLs), including those for ethanol-related traits, have been mapped in the mouse. In light of rapidly developing tools and resources, we briefly review the strategy for identifying the genes underlying these QTLs. We note that positional cloning will soon be a matter of testing candidate genes rather than discovering genes; therefore, we describe a ``congenic test' to support that a candidate gene is indeed a QTL. Considering the rapid development of congenics and mutants, we also identify four areas of investigation—phenotypes, ethanol specificity, environment, and gene interactions—that might be exploited during the course of positional cloning to gain insights into QTL pathways. In particular, we note that multiple mutants of nearly every major neurotransmitter pathway have now been made. These mutants are not only useful for phenotypic tests, but also could be used to conduct ``gene dependence' tests of QTLs. We also consider potential applications for the very recently developed ability to clone mice. Received: 15 September 1998 / Accepted: 8 October 1998     

What can patterns of differentiation across plant genomes tell us about adaptation and speciation?

Genome scans have become a common approach to identify genomic signatures of natural selection and reproductive isolation, as well as the genomic bases of ecologically relevant phenotypes, based on patterns of polymorphism and differentiation among populations or species. Here, we review the results of studies taking genome scan approaches in plants, consider the patterns of genomic differentiation documented and their possible causes, discuss the results in light of recent models of genomic differentiation during divergent adaptation and speciation, and consider assumptions and caveats in their interpretation. We find that genomic regions of high divergence generally appear quite small in comparisons of both closely and more distantly related populations, and for the most part, these differentiated regions are spread throughout the genome rather than strongly clustered. Thus, the genome scan approach appears well-suited for identifying genomic regions or even candidate genes that underlie adaptive divergence and/or reproductive barriers. We consider other methodologies that may be used in conjunction with genome scan approaches, and suggest further developments that would be valuable. These include broader use of sequence-based markers of known genomic location, greater attention to sampling strategies to make use of parallel environmental or phenotypic transitions, more integration with approaches such as quantitative trait loci mapping and measures of gene flow across the genome, and additional theoretical and simulation work on processes related to divergent adaptation and speciation.     

Quantitative Trait Loci for Metabolic Syndrome in the Hypertension Genetic Epidemiology Network Study

As part of the Hypertension Genetic Epidemiology Network study, genome scans were performed in two ethnicities on the categorical metabolic syndrome (MetS). Genome scans were performed also on the factor scores produced by factor analysis (quantitative MetS). Heritabilities were highest for the obesity‐insulin (INS) factor and lowest for blood pressure (BP) and central obesity. Seventeen unique putative quantitative trait loci (QTLs) yielded logarithm of the odds ratio (LOD) scores in excess of 1.7, 8 for blacks and 9 for whites. Important QTL findings in whites included an LOD score of 3.19 on chromosome 15q15 for the BP factor, 3.08 on chromosome 8p23 for the lipids‐INS factor, and 3.07 on chromosome 3p26 for the obesity‐INS factor. In blacks, after excluding type 2 diabetics, important QTLs were identified, including an LOD score of 2.77 on 13p12 for the obesity‐INS factor and 2.63 on chromosome 11q24 for the lipids‐INS factor. Categorical MetS had lower results than quantitative MetS. Notably, several loci identified overlap with those identified in other studies for a single or group of traits. The most promising candidate loci on 11q24 for lipids‐INS and 13p12 for obesity‐INS in blacks, 8p23 for lipids‐INS, 14q24 for obesity‐INS, and 15q15 for BP in whites warrant further investigation.