Introduction

This 1999 update of the status of the human obesity gene map is the sixth in this series, which began as a chapter in the proceedings of the 7th International Congress on Obesity held in 1994 (1) followed by four subsequent yearly updates published in Obesity Research (2, 3, 4, 5). The present review provides an overview of the data reported from peer-reviewed papers as of the end of October 1999, on human obesity genes and markers. The review incorporates data accumulated from five lines of evidence: 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 markers.

The current update includes reports that have dealt with an extended panel of phenotypes pertaining to obesity, including body mass index (BMI), percent body fat, fat mass, skinfold thicknesses, and fat free mass or phenotypes of leanness. Negative findings for candidate genes and markers are not incorporated in this version of the map but they are briefly mentioned when available to us.

In this year's review, we are using the nomenclature and gene symbols as defined by the HUGO Nomenclature Committee (6). As for chromosomal locations, we used the information from the Genome Data Base (7) and the Genetic Location Database (8).

Single Gene Mutations

Because of significant progress in the characterization of the human genes first described in single-gene mutation rodent models and the recent study implicating Tubby in intracellular signaling by insulin (9), we have decided to reinstate the table describing these genes (Table 1). On the other hand, because progress in identifying specific genes involved in several of the syndromes related to obesity and the ever-expanding number of candidate genes potentially causing the disease, we have modified and updated the presentation of this section in this year's review. A section on single gene mutations will deal with syndromes in which obesity is clearly the dominant clinical feature (Table 2), whereas a Mendelian disorder section will review all syndromes found in the Online Mendelian Inheritance in Man (OMIM) database in which obesity or abnormal fat distribution is a related but nondominant clinical feature element (Table 3).

Table 1 - Single-gene mutation rodent models of obesity.

Full table

Table 2 - Cases of human obesity caused by single-gene mutations.

Full table

Table 3 - Obesity-related Mendelian disorders with known map location.

Full table

Since last year's review, there have been very few new single gene cases published. The only major contribution has been by Hinney et al. who described six female obese subjects with mutations in the MC4R gene (10), two with the already known CTCT deletion at codon 211, and four others (two probands and their respective mothers) with a novel mutation at position 35 leading to a premature stop codon generating a truncated protein product. Seven missense mutations in MC4R of unknown significance in seven other extremely obese subjects (BMI > 99th percentile) were also described (10). Another group (11) reported on a 43-year-old woman with a BMI of 57 kg/m², heterozygous for an Ile137Thr polymorphism in the MC4R gene, but with other carriers not showing obesity.

The Hinney group (10) also reported on a study for mutations in the POMC gene. One female subject (14.2 years old, BMI 32.2 kg/m²) was homozygous for a 9-basepair (bp) insertion between codons 73 and 74, whereas another female obese adolescent (aged 16.5 years, BMI 35.9 kg/m²) was a compound heterozygote for a 6-bp insertion at codon 176, and a G to T transversion at nucleotide (nt) 7316 together with a missense change A-7341-G. Finally, one obese subject (BMI 36.4 kg/m²) was heterozygous for an 18-bp insertion between codons 73 and 74. However, these polymorphisms were not demonstrated to be causative for the obesity observed among these subjects.

In two other genes, UCP3 and DRD4, polymorphisms have been reported with unclear clinical implications. In 1994, Nöthen et al. (12) found a male homozygous for a 13-bp deletion in exon 1 of the DRD4 gene, which causes a premature stop codon and probably a nonfunctional protein. The subject was obese (BMI 37 kg/m² at age 50), had consistent slight hypothermia (rectal temperature of 35.4°C) and showed signs of autonomic hyperactivity with severe dermatography and excessive sweating, and left-sided acoustic neurinoma. In an association study on UCP3 gene polymorphisms in whites, Africans, and African-Americans, Argyropoulos et al. (13) reported that three obese subjects from the same family (aged 20, 14, and 11 with BMIs of 44.7, 29.2, and 26.1 kg/m², respectively) were homozygotes for a missense change in exon 3 (Val102Ile). In another family, one compound heterozygote (age 16 and BMI of 51.8 with Type 2 diabetes mellitus) showing a stop codon in exon 4 (Arg143X) and a missplicing of exon 6 was also observed (13). Although the exon 6 polymorphism was associated with obesity and metabolic changes (see "Association Studies"), the demonstration that these variants are causative of a single gene mutation syndrome remains to be established.

The family of Turkish origin, showing a mutation in leptin gene (LEP) and already described by Strobel et al. in 1998 (14), was more thoroughly investigated by Ozata et al. (15), who found an additional female member carrying the same mutation. Of particular interest this year, a first case has been reported of specific treatment for a genetically caused obesity syndrome. In September 1999, Farooqi et al. (16) described the significant clinical response to recombinant human leptin in a 9-year-old girl with severe obesity and congenital leptin deficiency. Over a 12-month period, the patient lost 16.4 kg of body weight of which 15.6 kg were fat mass (baseline body weight of 94.4 kg and BMI of 48.2 kg/m²).

Mendelian Disorders

In this year's review, we are expanding this section with the inclusion of several new syndromes in which obesity or fat distribution anomalies are part of the clinical synopsis in the OMIM database, and for which chromosomal locations are known (Table 3). We have also added information on the most likely candidate gene polymorphisms and mutations for the syndromes when available.

Among the autosomal dominant diseases, there are three new additions to the summary table (Table 3). Albright's hereditary osteodystrophy (AHO) is characterized by obesity, rounded facies, short stature, and subcutaneous calcifications. Two phenotypical variants exist. One is pseudohypoparathyroidism (PHP) where hypocalcemia and hyperphosphatemia refractory to exogeneous parathyroid hormone (PTH) are present, owing to peripheral resistance to PTH (other hormone resistance conditions often also exist). The less severe form is pseudopseudohypoparathyroidism (PPHP), where no biochemical anomaly is observed. The disease is caused by reduced expression or altered function of the alpha-subunit of the Gs protein that couples receptors to adenylyl cyclase stimulation. A whole series of variations in the gene encoding this protein, GNAS1, have been reported: in exon 1 (17, 18), exon 4 (19), intron 5 (20), exons 7–8 (19, 21), exon 9 (22), intron-exon 10 (23, 24, 25), and exon 13 (26, 27). Also, in one study AHO was linked to markers on chromosome 15q11 (28), defining the new subtype AHO2.

In the family of hereditary insulin resistance syndromes (IRS), there is Type C IRS in which obesity accompanies hyperandrogenism, insulin resistance, and acanthosis negricans (HAIR-AN syndrome) in the absence of autoimmunity. This type differs from Type A IRS where obesity is absent, but overlaps with the polycystic ovary syndrome (PCOS) in which the same clinical features are present. Many mutations in the gene encoding the insulin receptor (INSR) have been described in IRS but most have been found in subjects with forms other than Type C or in nonobese subjects. However, some studies reported variations in clearly obese subjects: an exon 3 deletion (29), an exon 14 deletion (30, 31), and mutations in exon 20 (32, 33). On the other hand, several reports have failed to find mutations in the INSR gene in IRS Type C patients (34, 35, 36).

The last addition is the thyroid hormone resistance syndrome (THRS), where a mutation in the THRB gene was reported by Behr et al. in 1997 (37). We now include this case in the present section because obesity was not the dominant feature of the patient.

For the other autosomal dominant syndromes, several advances have occurred. In achondroplasia, the most common genetic form of dwarfism in which obesity is highly prevalent (38), the causal gene was reported to be fibroblast growth factor receptor 3 (FGFR3) (39, 40, 41, 42). Almost all patients have a G to A transition or G to C transversion at nt 1138.

In the Prader-Willi syndrome, most patients have 3- to 4-megabase (Mb) deletions in the paternally derived chromosome at 15q11.2, and most of the remainder have maternal disomy, i.e., two maternally derived chromosomal regions at 15q11. However, a small number of patients have microdeletions in the imprinting center at 15q11-q13. Two groups (43, 44) recently narrowed down the location of the latter causal defects to a critical region of less than 4.3 kb spanning the promoter and exon 1 of the small nucleoriboprotein N (SNRPN) gene, or the exons 2 and 3 of the same gene. A new form of Angelman syndrome with obesity was described this year by Gillessen-Kaesbach et al. (45). The syndrome, characterized by muscular hypotonia and mild mental retardation, is caused by an imprinting defect in the same chromosomal region as the PWS, at 15q11-q12.

For the ulnar-mammary syndrome (UMS), mutations in exons 1 and 2 of the TBX3 gene were found in 1997 in families with members presenting the syndrome (46). Finally, a new linkage study in white Germans confirmed the linkage of familial partial lipodystrophy to chromosome 1q21-q22, with a multipoint lod score of 6.27 near marker D1S2721 (47).

In the autosomal recessive disease category, three syndromes have been added. The Berardinelli-Seip syndrome is a rare disorder characterized by a near complete absence of adipose tissue. Subjects are highly insulin resistant, hypertriglyceridemic, with acanthosis negricans and Type 2 diabetes mellitus at a young age. A recent study in families of various ethnic backgrounds found linkage to loci D9S1818 and D9S1826, with a maximal Lod score of 5.4 (48).

The carbohydrate-deficient glycoprotein syndrome type 1A (CDGS1A) or Jaeken syndrome is caused by defective glycosylation of glycoconjugates resulting in severe encephalopathy with axial hypotonia, abnormal eye movements, psychomotor retardation, peripheral neuropathy, cerebellar hypoplasia, retinosis pigmentosa, nipple retraction, hypogonadism, and lipodystrophy. One group reported in 1997 on 11 different missense mutations in the human phosphomannomutase 2 (PMM2) gene, found only in the affected subjects (49).

In the Fanconi-Beckel syndrome (FBS), patients have sparse subcutaneous fat as well as hepatorenal glycogen accumulation due to impaired utilization of glucose and galactose. Mutations in exons 3, 6, and 8 of the SLC2A2 gene that encodes the facilitative glucose transporter 2 were found by Santer et al. (50).

New results were published on Alstrom syndrome, where the causal region was narrowed down to a 6.1-cM interval between D2S291 and D2S2114 on chromosome 2 in a linkage study performed on a consanguineous pedigree of North African origin (51). In the Bardet-Biedl syndrome, a fifth locus was mapped to 2q31 in a Newfoundland pedigree (52, 53) and the unconventional myosin IXA (MYO9A) gene was investigated with inconclusive results in a study on BBS4 families (54).

The last category deals with X-linked diseases. No new syndrome has been reported in this category. For the Borjeson-Forssman-Lehmann syndrome, the fibroblast growth factor 13 (FGF13) gene, previously named fibroblast growth homologous factor 2, was characterized and mapped to the same Xq26 location as the syndrome, but its role remains to be explored (55). In the Simpson-Golabi-Behmel syndrome (SGBS), a new chromosomal region was mapped, at Xp22, in a severely affected family (56). Moreover, deletions have been reported in several exonic areas of the glypican-3 and glypican-4 (GPC3 and GPC4) genes located side by side at Xq26, in SGBS families (57, 58, 59, 60, 61, 62) and several of these were summarized in 1998 by Neri et al. (63).

Quantitative Trait Loci (QTL) from Crossbreeding Experiments

The number of animal QTLs linked to body weight or body fat has increased by 25 since the last review (Table 4). Five QTLs linked to energy expenditure in mice, and one QTL to food intake in chickens have also been reported. A total of 98 animal QTLs have now been evidenced and their equivalent syntenic regions in humans, when they can be determined with available maps, are shown in Table 4. We have proposed acronyms for QTLs to facilitate their inclusion in the map when none was provided by the authors. Overall, the results of five mouse, three rat, three pig, and one chicken novel crosses have been published. Some existing mouse and pig crosses have been further investigated as well.

Table 4 - QTLs reported for animal polygenic models of obesity with their putative syntenic locations in the human genome.

Full table

From the mouse cross JU/CBA x CFLP (P6 line), originally selected for growth rate, a strong QTL explaining 17% to 20% of the body weight at 10 weeks was observed on the X chromosome (QbwX; [(64) ]). It could correspond to the previously described QTL Bw3 of Dragani et al. (65). Four mouse crosses involving diabetic strains have been reported. Taylor et al. (66) have produced a new cross between the diabetic KK/H1Lt and the C57BL/6J strains and identified two QTLs related to adiposity, in females (Obq5) or males (Obq6), and a third to body weight and inguinal fat (KK7). Suto et al. (67) from the cross KK-A(y) (diabetic) x C57BL/6J have detected a QTL related to body weight (Bwq1) and to body weight and adiposity (Bwq2), whereas two QTLs (Nidd5 and Nidd6) related to body weight were observed from the cross involving the diabetic TSOD and BALB/cA strains (68). Finally, in the cross NSY (diabetic) x C3H/He, a QTL (Nidd3nsy) related to epidydimal fat weight was observed (69).

From the cross C57BL/6J x DBA/2J, previously characterized for body weight at 6 weeks (70), four new QTLs related to percent fat predicted from body weight and dry weight carcass, have been uncovered (Pfatp4, Pfatp6, Pfatp13, and Pfatp15 [(71) ]). In an experiment using C57BL/6J x DBA/2J, QTLs for energy expenditure were investigated using the heat loss measured in a metabolic chamber as the phenotype (72). Five QTLs (Hlq1 to Hlq5) were uncovered with heat loss, one with gonadal fat pad (Fatq1), and two with brown fat levels (Batq1 and Batq2 [(72) ]).

One new rat cross involved the diabetic OLETF and the BN strains, and two between the hypertensive strains Dahl or SHR with the Milan normotensive (MNS) and BB/OK strains, respectively, have been produced. QTLs with body weight were observed from the OLETF (Dmo1 [(73) ]), the Dahl (DAHL3 [(74) ]), and the SHR (SHR1 and SHR4 [(75) ]) crosses.

The first QTLs reported in pigs from the cross between European wild boar x Large white (76) have been confirmed in additional studies using a similar cross, with back and abdominal fat (77), and with visceral, abdominal, and percent fat (FAT1 [(78) ]). Moreover, this QTL was also observed in the different cross Meishan x Large white (79). On the other hand, a new QTL with backfat depth and possibly involving the insulin-like growth factor 2 (IGF2) gene, has been uncovered in a Wild boar x Large white cross (80). Finally, three QTLs with backfat thicknesses have been uncovered in a Meishan x Landrace and a Minghu x Large White crosses (SSC7 [(81) ]), and a Meishan x White composite (SSC1, SSC7, and SSCX [(82) ]). As to the chicken, a first QTL related to food intake has been observed in a cross between different strains from White Plymouth Rock stocks (AFIFA1 [(83) ]).

We have defined, when not provided by the authors, the putative syntenic relationships with human chromosomes for the QTLs identified in Table 4. To establish the synteny, the position, according to the Mouse Genome Database (MGB) from the Jackson Laboratory (84), of the markers defining the QTL, was compared to the equivalent region in the human genome using the integrated linkage maps of the Mouse/Human homology maps (85). For the rat, maps described in Yamada et al. (86) and Jacob et al. (87) were used, whereas the map from the Animal Genome Database in Japan (88) was used for the pig. No information was found for the chicken.

Association Studies

The evidence for association between candidate genes and obesity-related phenotypes is summarized in Table 5. Studies published over the past year have shown associations of BMI and body weight with polymorphisms in UCP2 and UCP3 (13, 89, 90), PPARG (91, 92, 93), ADRB2 (94, 95, 96, 97), APOA4 (98), CD36L1 (99), IRS1 (100), GNB3 (101, 102, 103), and ADA (104). Fat mass and/or percent body fat were associated with markers of ADRB3 (105), IGF1 (106), and AGT (107), whereas fat-free mass showed associations with LEPR (108) and UCP1 (106). In addition, the PON2 gene has been reported to be associated with birth weight (109). Changes in BMI and body weight have been associated with variation in the PPARG (110), IRS1 (100), and UCP1 (111) genes. Weight gain during pregnancy was associated with the ADRB3 gene polymorphism (112). Plasma leptin levels have also found to be associated with variation in the POMC (113) and the IRS1 (114) genes. Basal metabolic rate has been reported to be associated with the ADRA2B gene (115) and positive associations were found between respiratory quotient and markers of the ATP1A2 (116) and the UCP3 (13) genes. Finally, a UCP2 gene polymorphism was associated with 24-hour energy expenditure, spontaneous physical activity, non-protein respiratory quotient, and fat oxidation (117).

Table 5 - Evidence for the presence of an association between markers of candidate genes with BMI, body fat, and other obesity-related phenotypes.

Full table

In addition to the simple associations between obesity-related phenotypes and individual gene markers, some studies tested for gene-environment and gene-gene interactions. In a large cohort of men from northern France, highly significant associations between body weight, BMI, waist and hip circumferences, and the Gln27Glu polymorphism of the ADRB2 gene were observed in sedentary men but not in those who were physically active (95). Additive effects of polymorphisms in the UCP1 and ADRB3 genes on weight loss were reported in obese Japanese (111) and Finnish (118) women. Moreover, data from the Atherosclerosis Risk in Communities Study cohort suggest that there is an interaction effect between the IRS1 and FABP2 gene variants on BMI (100).

In addition to the 89 studies with positive findings summarized in Table 5, we uncovered 35 studies showing no associations between obesity-related phenotypes and selected candidate genes. Among the negative studies, the most frequent ones were those performed with markers of ADRB3 (ten studies) (119, 120, 121, 122, 123, 124, 125, 126, 127, 128), PPARG (three studies) (129, 130, 131), and LEP (three studies) (132, 133, 134). Other markers yielding negative findings were related to POMC (135, 136); MC4R (11, 137); UCP1 (138, 139); UCP2 (140); UCP3 (141); ADRB2 (142, 143); HTR1B and HTR7 (144); CNTF (145); IRSI (146); CCKAR (139); FABP2 (147); NPY (148); ESR2 (149); GLP1R, ASIP, and MC5R (137); TNFA (150); and the mitochondrial DNA D-loop region (151).

Linkage Studies

Table 6 presents a summary of the studies providing evidence of linkage with obesity-related phenotypes. The results of two other genome-wide scans performed in French (152) and American (153) families became available, adding to those already reported in Pima Indians (154, 155, 156) and in Mexican-Americans (157). In order to distinguish linkages from genomic scans and markers not surrounding known candidate genes, we used "QTL" in the gene column, and indicated the name of the markers closest to the QTL. One of them was performed on 158 nuclear families from Paris-Lille (152), using a total of 380 microsatellite markers with an average distance between markers of 9.1 cM (range 1.5 to 28.8 cM). The strongest evidence of linkage with obesity (BMI > 27 kg/m²) was found on chromosome 10p with a maximum Lod score value of 4.85 near markers D10S197 and D10S611. Additional evidence of linkage was found with plasma leptin levels at 2p21 (Lod = 2.68 with markers D2S165 and D2S367) and 5q (Lod = 2.93 with marker D5S426). Another genome-wide scan was reported based on 513 individuals from 92 families ascertained through an extremely obese proband (BMI 40 kg/m²), with the addition of 32 families for the mapping of the region providing the most promising evidence of linkage (153). A total of 354 microsatellite markers, on average 10.1 cM apart, were genotyped and tested for linkage with BMI and percent body fat measured by bioelectric impedance. Significant evidence of linkage using single-point and multipoint methods was found on chromosome 20q13 near markers D20S107, D20S211, and D20S149 (153).

Table 6 - Evidence for the presence of linkage with obesity-related phenotypes.

Full table

The evidence of linkage previously reported with plasma leptin in Mexican-Americans on 2p21 (157) was substantially increased (Lod = 7.46) by typing six additional markers (113) and replicated in African-American families with marker D2S1788 (158) and in the genomic scan of the Paris-Lille families (152). Another linkage study performed in Mexican-Americans with markers surrounding the ADRB3 locus found significant evidence of linkage (Lod = 3.21) with BMI between D8S1121 and the ADRB3 gene (Trp64Arg polymorphism), some 2.5 cM telomeric to the ADRB3 locus (159). In a sib-pair linkage study of 15 candidate genes of food intake regulation, glucose and insulin metabolism, energy expenditure, and adipose tissue metabolism performed in French families with morbid obesity (160), significant evidence of linkage was found between the LIM/homeodomain islet-1 (ILS1) gene on 5q and obesity (p = 0.03), BMI (p = 0.001), and leptin levels (p = 0.0003), as well as between the CCKBR gene and plasma leptin (p = 0.01). All the other genes tested (ADRB3, UCP1, PPARG, LIPE, LPL, APOC2, TNFA, CCKAR, GLP1R, FABP2, CDX3, IRS1, and CPT1) yielded negative findings (160). In a similar study involving polymorphisms within or near seven candidate genes of obesity typed in 302 subjects from 59 Mexican-American families (161), weak evidence of linkage (p = 0.048) was found between a marker (D7S2190) located within 200 kb of the NPY gene and a composite variable obtained by a principal component analysis of body weight and anthropometric measures, and between a marker located within 290 kb of the LEP gene and waist-to-hip girths ratio (161). No significant evidence of linkage was found with markers of the LEPR, NPYY1, GLP1, GLP1R, and UCP1 genes (161).

Two studies performed in the Québec Family Study data reported significant linkages between body fat variables and polymorphims in the LEPR gene (108) and between respiratory quotient and the ATP1A2 gene on 1q22-q25 (116). In a study of 105 Finnish obese sib pairs, markers covering a 14-cM region around the MC4R gene were found to be linked with obesity (162). Finally, evidence of linkage was reported between abdominal visceral fat measured by computed tomography and the IGF1 gene on chromosome 12q22-q23 (106).

Conclusions

Figure 1 depicts the human obesity gene map and incorporates the loci from single-gene mutation rodent models of obesity, human obesity cases due to single-gene mutations, QTLs from crossbreeding experiments and genome-wide scans, all relevant Mendelian disorders that have been mapped to a chromosomal region, and genes or markers that have been shown to be associated or linked with an obesity phenotype.

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, with chromosomes 14 and 21 showing only one putative locus. Results from genomic scans reveal several new human QTLs related to body fat, energy expenditure, and respiratory quotient. The number of animal QTLs increased from 67 to 98. Results from association studies with candidate genes indicate that the number of candidate genes associated with obesity-related phenotypes has increased from 26 to 40 since the 1998 update.

The number of genes and other markers associated or linked with human obesity phenotypes continues to expand and reaches now well over 200. Of course, some of these loci will turn out to be more important than others and many will eventually be proven to be false-positive. The main task, including the identification or the positional cloning of the QTL genes, remains to identify the combination of genes and mutations that are contributing most to human obesity and to define under which environmental circumstances.

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Appendices

Appendix

Table 7

Table 7 - Symbols, full names, and cytogenetic location of genes and loci of the 1999 Human Obesity Gene Map.

Full table

Acknowledgments

The research of the authors on the genetics of obesity is funded by the Medical Research Council of Canada (PG-11811, MT-13960, and GR-15187). C. Bouchard is supported by the George A. Bray Chair in Nutrition. Thanks are expressed to Diane Drolet, MSc, for her dedicated contribution to the compendium and the development of the manuscript, and to Sophie Gagnon for her help in gathering references. The list of genes and markers currently in the map as well as the pictorial representation of the map is also available on the Web site of the Donald B. Brown Research Chair on Obesity at the following address: http://www.obesity.chair.ulaval.ca/genes.html.