Review
The Human Obesity Gene Map: The 2000 Update
Louis Pe´russe,* Yvon C. Chagnon,* S. John Weisnagel,* Tuomo Rankinen,† Eric Snyder,† John Sands,† and Claude Bouchard†
Abstract number of negative studies, which are only partially re- PE´ RUSSE, LOUIS, YVON C. CHAGNON, S. JOHN viewed here, is also on the rise. WEISNAGEL, TUOMO RANKINEN, ERIC SNYDER, JOHN SANDS, AND CLAUDE BOUCHARD. The human Key words: association, linkages, QTL, genes, Mende- obesity gene map: the 2000 update. Obes Res. 2001;9: lian syndrome 135–168. This report constitutes the seventh update of the human Introduction obesity gene map incorporating published results up to the This is the seventh update in this series on the status of end of October 2000. Evidence from the rodent and human the human obesity gene map. It incorporates the material obesity cases caused by single-gene mutations, Mendelian published by the end of October 2000. Previous reviews disorders exhibiting obesity as a clinical feature, quantita- have been published (1–6). The review has expanded con- tive trait loci uncovered in human genome-wide scans and siderably and continues to incorporate evidence from sev- in cross-breeding experiments in various animal models, eral research approaches, with each approach constituting a and association and linkage studies with candidate genes section heading. As in previous compendia, the present and other markers are reviewed. Forty-seven human cases synthesis includes sections dealing with single human gene of obesity caused by single-gene mutations in six different mutations, genetically unidentified Mendelian disorders, genes have been reported in the literature to date. Twenty- quantitative trait loci (QTLs) from rodent and other animal four Mendelian disorders exhibiting obesity as one of their model studies, association studies in humans with specific clinical manifestations have now been mapped. The number genes and mutations, human linkage studies including ge- of different quantitative trait loci reported from animal nome scans whose goals are to identify QTLs of obesity or models currently reaches 115. Attempts to relate DNA obesity-related phenotypes, and a refined pictogram of the sequence variation in specific genes to obesity phenotypes 2000 human obesity gene map. The references to each entry continue to grow, with 130 studies reporting positive asso- in the current human obesity gene map are provided for ciations with 48 candidate genes. Finally, 59 loci have been convenience. linked to obesity indicators in genomic scans and other The review includes publications that have dealt with a linkage study designs. The obesity gene map reveals that variety of phenotypes pertaining to obesity, including body putative loci affecting obesity-related phenotypes can be mass index (BMI), body fat mass, percentage of body fat, fat-free mass, skinfolds, resting metabolic rates, plasma found on all chromosomes except chromosome Y. A total of leptin levels, and other components of energy balance. As in 54 new loci have been added to the map in the past 12 previous updates, negative findings are not systematically months and the number of genes, markers, and chromo- reviewed but are briefly introduced when such data were somal regions that have been associated or linked with available to us. human obesity phenotypes is now above 250. Likewise, the In this year’s review, we are using gene symbols and chromosomal locations given in the Locus Link website
Submitted for publication December 8, 2000. (http://www.ncbi.nlm.nih.gov/LocusLink) available from Accepted for publication in final form December 8, 2000. the National Center for Biotechnology Information, which *Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of provides the official nomenclature of genetic loci. Medicine, Laval University, Sainte-Foy, Que´bec, Canada; and †Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana. We renew our request for feedback and comments on the Address correspondence to Louis Pe´russe, PhD, Department of Social and Preventive part of the investigators who are interested in any aspects of Medicine, Division of Kinesiology-PEPS Building, Laval University, Sainte-Foy, Que´bec, G1K 7P4, Canada. E-mail: [email protected] the gene map and who would like to contribute to future Copyright © 2001 NAASO editions of this publication. The electronic version of this
OBESITY RESEARCH Vol. 9 No. 2 February 2001 135 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al. publication will be available at the following address: http:// tion with central adiposity, we have reviewed the hereditary www.obesity.chair.ulaval.ca/genes.html. An expanded and growth hormone and pituitary hormone deficiency syn- more extensively cross-referenced version of the map can dromes, for which several causal genes have been well- be accessed at http://www.eureka.pbrc.edu. characterized in the last decade. We have only retained those syndromes for which overall or central obesity is clearly specified in the reports. Single-Gene Mutations In the autosomal recessive category, isolated growth hor- We have added to single-gene mutation rodent models mone deficiencies with mutations in the growth hormone- (Table 1) the attractin (Atrn) gene from the Mahogany releasing hormone receptor gene have been described. mutation that suppresses diet-induced obesity. In humans, Wajnrajch et al. (12) reported on two children with predom- ATRN is located at 20p13 and encodes a transmembrane inantly truncal obesity carrying a G 3 T transversion at nt form of attractin (7). This last year has seen the discovery of another probable 265, resulting in a Glu72Stop mutation and a truncated 3 gene mutation explaining a human obesity syndrome (Table receptor. Salvatori et al. (13) described a G A transition Ј 2). Holder et al. (8) described a severely obese girl with a of nt 1 of the 5 splice site at the beginning of IVS1 in 30 weight of 47.5 kg at 67 months of age (ϩ9.3 SD) and a affected subjects of Brazilian origin with increased abdom- height of 1.27 m (ϩ3.2 SD); no other anomalies were inal fat accumulation and severe growth retardation. reported. She carried a de novo balanced translocation be- In the combined pituitary hormone deficiency syn- tween chromosomes 1 and 6 (karyotype 46,XX,t(1; dromes, multiple endocrine axes can be affected with vari- 6)(p22.1;q16.2)), which disrupted the SIM1 gene, a critical able clinical expression. In particular, hereditary growth transcription factor for the formation of supraoptic and hormone deficiency syndrome and central hypothyroidism paraventricular hypothalamic nuclei in mice. The latter nu- can lead to truncal obesity. The “Prophet of Pit-1” or clei are well known to be involved in energy homeostasis. PROP1 gene, controlling the ontogenesis of pituitary neu- The patient was heterozygous for a silent C 3 T substitu- roendocrine cells, is involved in several reported cases of tion at nucleotide (nt) 1328 in exon 9, presumably associ- combined pituitary hormone deficiency syndromes. In ated with a loss of function of SIM1. Her energy expendi- 1999, Rosenbloom et al. (14) reported on eight subjects with ture was normal for her age and weight, implying that the a 2-bp 296delGA deletion, three of whom were over the mutation probably affected energy intake. 90th percentile for BMI with respect to height. Mendonca et Among the previously reported monogenic obesity syn- al. (15) described two subjects carrying a 2-bp 301delAG dromes, the only new published cases have been on carriers deletion, both of whom had marked decreases in height but of mutations in the melanocortin-4 receptor (MC4R) gene. increases in weight relative to height. The German group that reported on six individuals in 1999 Among the previously reported syndromes, in the auto- (9) expanded their study to three families, identifying a total somal dominant category, the major advance in the last year of 19 carriers of either a 4-base pair (bp) deletion at codon was the discovery of a gene explaining Dunnigan-type 211 or a nonsense mutation at codon 35 (10). However, familial partial lipodystrophy, a syndrome in which periph- obesity status differed between carriers, suggesting variable eral subcutaneous fat is absent. Cao and Hegele (16) de- penetrance. In a population of 209 severely obese (BMI of scribed five Canadian patients each carrying a novel G 3 A Ͼ 2 40 kg/m ) French subjects, Vaisse et al. (11) reported on change at codon 482 in exon 8 (missense mutation R482Q) 8 carriers of eight different mutations in the MC4R gene not in the lamin A/C gene (LMNA), which undergoes alterna- found in 366 normal weight controls. Several of the muta- tive splicing to produce the nuclear lamin proteins lamin A tions appeared to have a functional impact. Thus far, of a and lamin C. No unaffected members of the five families total of 47 cases of monogenic forms of obesity involving carried the mutation. 19 mutations in six different genes, MC4R mutations seem Regarding other syndromes, several new mutations in the to be the most frequent, with a total of 11 mutations respon- GNAS1 gene were reported by Aldred and Trembath (17), sible for 34 cases. as well as a review of published mutations in patients with Albright hereditary osteodystrophy, a disorder in which Mendelian Disorders obesity is one of the defining features. Prader–Willi syn- Progress is ongoing in identifying genes or narrowing drome (PWS) remains a subject of intense research, with a down the loci associated with the various adiposity-related French group demonstrating the possible involvement of a Mendelian disorders described in the Online Mendelian novel imprinted gene in the PWS locus, the NDN gene, Inheritance in Man database; a total of 24 syndromes with which is the human homologue of the mouse brain-specific known map locations are given in Table 3. nectin protein gene (18). Another group (19) reported a In this year’s update, because of the importance of growth family with PWS in which affected members carried only hormone on body fat distribution, in particular its associa- submicroscopic deletions in the SNRPN gene and not in
136 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 1. Single-gene mutation rodent models of obesity*
Rodent Human Mutations† Chromosome Genes Inheritance Chromosome Genes Gene product References Diabetes (db)‡ 4 Lepr Recessive 1p31 LEPR Leptin receptor 140,141 Fat (fat) 8 Cpe Recessive 4q32 CPE Carboxypeptidase E 142 Obese (ob) 6 Lep Recessive 7q31.3 LEP Leptin 143 Tubby (tub) 7 Tub Recessive 11p15.5 TUB Insulin signaling protein 144–146 Mahogany (mg) 2 Atrn Recessive 20p13 ATRN Attractin 7,147 Agouti yellow (Ay) 2Ay Dominant 20q11.2–q12 Agouti signaling protein 148
* Status as of October 2000. † The strain carrying the adult (ad) dominant mutation on chromosome 7 is now extinct. ‡ Homologous to rat fat (fa)/corpulent (cp).
nearby loci, therefore confirming previous reports (20,21) region between markers D11S1883 and D11S4944 on that the PWS imprinting center is located close to that gene. chromosome 11. Young et al. (23) further reduced the In the autosomal recessive category, progress was BBS1 interval to a 1-cM region between markers made in Bardet–Biedl syndrome (BBS) patients. Katsanis D11S1883 and D11S4940, surrounding the phosphor- et al. (22) narrowed down the type 1 (BBS1) locus, ylase glycogen muscle locus, in a study of families from through linkage and haplotype analysis in 91 pedigrees of Newfoundland, Canada. This same Canadian group also North American and European origin, to a 1.8-megabase narrowed down the BBS type 3 locus through haplotype
Table 2. Cases of human obesity caused by single-gene mutations
Age (range) years BMI (range) kg/m2 References ءGene Location Mutation N LEPR 1p31 G3A (exon 16) 3 13–19 52.5–71.5 149 POMC 2p23.3 G7013T and C7133⌬ (exon 3) 2 3–7 N/A 150 C3804A (exon 2) PCSK1 5q15-q21 Gly483Arg A3Cϩ4 (intron 5) 1 3 N/A 151 SIM1 6q16.3-q21 C3T nt 1328 (exon 9) 1 6.6 29.5 8 LEP 7q31.3 G398⌬ (codon 133) 2 2–8 36.6–45.8 152,153 C3T (codon 105) (exon 3) 4 6–34 32.5–55.8 154,155 MC4R 18q22 ⌬CTCT nt 631–634 (codon 211) 10 4–81 27.7–41 9,10,156 GATT insertion at nt 732 (codon 246) 5 11–58 30–57 157 C1O5A Tyr35X 11 8–64 25.9–56.6 9,10 47-48insG 8 28–52 41.5–64.5 11 A31G C52T C449T A508G C493T T749A T902C
N/A, not available. .N, number of published cases ء
OBESITY RESEARCH Vol. 9 No. 2 February 2001 137 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 3. Obesity-related Mendelian disorders with known map location*
OMIM Mode of inheritance No. Syndrome Locus Candidate gene References Autosomal dominant 100800 Achondroplasia (ACH) 4p16.3 FGFR3 158–161 103580 Albright hereditary osteodystrophy 20q13.2-q13.3 GNAS1 17,162–172 (AHO) 300800 103581 Albright hereditary osteodystrophy 2 15q N/A 173 (AHO2) 105830 Angelman syndrome with obesity (AGS) 15q11-q13 N/A 174 147670 Insulin resistance syndromes (IRS) 19p13.3-p13.2 INSR 175–182 122000 Posterior polymorphous corneal 20q11 N/A 183 dystrophy (PPCD) 151660 Familial partial lipodystrophy Dunnigan 1q21.2-q21.3 LMNA 16,184–186 (FPLD) 176270 Prader–Willi syndrome (PWS) 15q12 SNRPN NDN 18–21,187 190160 Thyroid hormone resistance syndrome 3p24.3 THRB 188 (THRS) 181450 Ulnar-mammary syndrome or Schinzel 12q24.1 TBX3 189 syndrome (UMS) Autosomal recessive 203800 Alstrom syndrome (ALMS1) 2p13-p12 N/A 190,191 209901 Bardet–Biedl syndrome 1 (BBS1) 11q13 N/A 22,23,192 209900 Bardet–Biedl syndrome 2 (BBS2) 16q21 N/A 192,193 600151 Bardet–Biedl syndrome 3 (BBS3) 3p13-p12 N/A 24,194 600374 Bardet–Biedl syndrome 4 (BBS4) 15q22.3-q23 MYO9A 192,195,196 603650 Bardet–Biedl syndrome 5 (BBS5) 2q31 N/A 197,198 605231 Bardet–Biedl syndrome 6 (BBS6) 20p12 MKKS 25,26 269700 Berardinelli–Seip congenital 9q34 N/A 199 lipodystrophy (BSCL) 216550 Cohen syndrome (COH1) 8q22-q23 N/A 200 212065 Carbohydrate-deficient glycoprotein type 16p13.3-p.13.2 PMM2 27,28,201 1a (CDGS1A) 227810 Fanconi–Bickel syndrome (FBS) 3q26.1-q26.2 SLC2A2 29–31,202 139191 Isolated growth hormone deficiency 7p15-p14 GHRH-R 12,13 (IGHD) 601538 Combined pituitary hormone deficiency 5q PROP1 14,15 (CPHD) X-linked 301900 Borjeson–Forssman–Lehmann syndrome Xq26 FGF13 203,204 (BFLS) 303110 Chroroideremia with deafness (CHOD) Xq21.1-q21.2 N/A 205,206 300148 Mehmo syndrome (MEHMO) Xp22.13-p21.1 N/A 207,208 300218 Mental retardation X-linked, syndromic Xp11.3-q22 N/A 33 7 (MRXS7) 300238 Shashi X-linked mental retardation Xq26-q27 N/A 32 syndrome (SMRXS) 312870 Simpson–Golabi–Behmel 1 (SGBS1) Xq26.1 GPC3, GPC4 34,209–215 Simpson–Golabi–Behmel 2 (SGBS2) Xp22 N/A 216 309585 Wilson–Turner syndrome (WTS) Xp21.2-q22 N/A 217
* Adapted from OMIM (Online Mendelian Inheritance in Man) computerized database. N/A, not available. Status as of October 2000.
138 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al. analysis to a critical 6-cM interval on chromosome 3 centage of fat on chromosomes 2, 12, 15, and X (35). between D3S1595 and D3S1753 (24). Finally, a new Five of the QTLs previously reported for late body BBS, type 6 (BBS6), mapping to 20p12, was described in weight gain (36) were replicated on chromosomes 4, 5, 7, the past year by two groups (25,26). Both groups found 9, and 10 in a second F2 intercross of the LG/J and SM/J the gene involved, known as the McKusick–Kaufman mouse strains (37). The Wistar Ottawa Karlsburg with syndrome gene. It encodes for a chaperonin protein that RT1u haplotype (W) of the major histocompatibility com- plays a role in protein integrity. Affected individuals were plex (WOKW) rat strain, which develops the main fea- either homozygotes or compound heterozygotes for several tures of syndrome X such as moderate hypertension, mutations in the McKusick–Kaufman syndrome gene. dyslipidemia, hyperinsulinemia, obesity, and impaired In carbohydrate-deficient glycoprotein syndrome type 1a, glucose tolerance (38), has been crossed to the Dark a disorder caused by defective glycosylation of glycocon- Agouti/Karlsburg strain. Two new QTLs (WOKW1 and jugates resulting in severe encephalopathy with hypogonad- WOKW2) related to body weight and BMI and located, ism and lipodystrophy, several new mutations in the phos- respectively, on chromosome 1 and chromosome 5 (39) phomannomutase (PPM2) gene were reported (27,28). have been reported. A QTL for body weight (Dmo1) Similarly, in the past year, three different groups (29–31) previously identified from a cross between the diabetic described several novel mutations in the solute carrier fam- OLETF ϫ BN rat strains (40) was replicated in a back- ily 2 gene (SLC2A2), also known as the GLUT2 gene, in cross to the OLETF strain (41). In addition, new QTLs patients with Fanconi–Bickel syndrome, in whom there is related to fat weight, body weight, or adipose index on sparse subcutaneous fat as well as hepatorenal glycogen chromosomes 1 (Dmo4), 3 (Dmo5), 6 (Dmo6p), 7 accumulation. (Dmo7p), and 11 (Dmo9 and Dmo10) were identified. In the last category, X-linked Mendelian disorders, two In a pig cross involving the obese Chinese Meishan breed new syndromes have been described. Shashi et al. (32) and lean Dutch White production lines, one QTL (SSCX) reported on a large American family in which seven males for back fat thickness and intramuscular fat content has been had mental retardation with characteristic dysmorphic fea- detected on chromosome X, near the phosphoglycerate ki- tures and obesity. Linkage analysis established linkage to nase 1 gene (42). In the same cross, paternally or maternally Xq26–27. Ahmad et al. (33) described a Pakistani family in expressed QTLs were also observed for back fat thickness which 10 males showed mental retardation, obesity, hypo- on chromosomes 2 (SSC2) and 7 (SSC7), and two other gonadism, and tapering fingers. Maximum linkage was ob- QTLs (SSC6p, SSC6q) were observed for intramuscular fat tained with the marker DXS1106. on chromosome 6 (43). Finally, in a mix of five different Finally, in Simpson–Golabi–Behmel syndrome type 1, in crosses (Meishan ϫ Duroc or Hampshire or Landrace; which affected individuals have elevated birth weight and Minzhu ϫ Hampshire or Landrace) analyzed previously height as well as prenatal and postnatal overgrowth with (44), a QTL for back fat thickness at the pituitary specific slight obesity, Veugelers et al. (34) reported on several point transcription factor 1 gene, encoding an essential transcrip- mutations and one exon deletion in the glypican-3 (GPC3) tional regulatory factor of growth hormone, prolactin, and gene in seven patients, predicting loss-of-function of the thyrotropin  subunit, was identified on chromosome 13 (45). GPC3 protein. We have defined, when not provided by the authors, the putative syntenic relationships with human chromo- QTLs from Cross-Breeding Experiments somes for the QTLs identified in Table 4. To establish the The number of animal QTLs linked to body weight or synteny, the position of the markers defining the QTL, body fat has increased by 17 since the last review (Table 4). according to the Mouse Genome Database from The A total of 115 animal QTLs have now been uncovered. Jackson Laboratory (Bar Harbor, ME) (46), was com- Their equivalent syntenic regions in humans, when they can pared with the equivalent region in the human genome be determined from available maps, are shown in Table 4. using the integrated linkage maps of the Mouse/Human When none was provided by the authors, we have proposed homology maps (47). For the rat, the maps described by acronyms for QTLs to facilitate their inclusion in the Yamada et al. (48) and Jacob et al. (49) were used. For map. Overall, the results of one mouse novel cross, two rat the pig and the chicken, maps from the Animal Genome novel crosses, and one pig novel cross have been published. Database in Japan (50) and from the U.S. Livestock Some existing rat and pig crosses have also been further Genome Mapping Projects (51) were used. investigated. A new mouse cross between outbred lines divergently Association Studies selected for 53 generations for high-fat (fat or F line) or The evidence for associations between candidate genes and low-fat (lean or L line), and presenting a 5-fold differ- obesity-related phenotypes is summarized in Table 5. Alto- ence in percentage of fat at 14 weeks of age, allowed the gether 130 studies have reported significant associations in- detection of four QTLs (Fob1 to Fob4) related to per- volving a total of 48 candidate genes. Studies published over
OBESITY RESEARCH Vol. 9 No. 2 February 2001 139 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 4. QTLs reported for animal polygenic models of obesity with their putative syntenic locations in the human genome*
Chromosomes
Crosses QTL Statistics Phenotypes Animal Human References Mouse Mus spretus ϫ Mob1 lod ϭ 4.2 6.5% Percent fat 7 16p12.1-p11.2 218 C57BL/6J Mob2 lod ϭ 4.8 7.1% Femoral fat 6 7q22-q31.3 Mob3 lod ϭ 4.8 7.0% Percent fat 12 14q31-q32 Mob4 lod ϭ 3.4 5.9% Mesenteric fat 15 5p13 Mouse NZB/B1NJ ϫ SM/J Mob5† lod ϭ 3.6 36% Body fat 2 20q12-q13 219 Mouse CAST/Ei ϫ C57BL/6J Mob6 lod ϭ 7.3 Subcutaneous fat 2 2q31-q37 220 Mob7 lod ϭ 5.7 Subcutaneous fat 2 2q23-q37 Mob8 lod ϭ 4.7 Body fat (%) 9 6q12-q13 Qlep lod ϭ 5.2 Leptin level (no obesity) 4 9p22 Bl/Bw lod ϭ 4.3/2.5 Body length/body weight 15 8q22-q23 Mouse AKR/J ϫ SWR/J Dob1 lod ϭ 4.5 N/A 4 1p36.13-p35 221 9p13 Dob2 lod ϭ 4.8 7% Adiposity 9 3p21 222 Dob3‡ lod ϭ 3.9 4% Adiposity 15 8q23-q24 Mouse A/J ϫ M. spretus ϫ Bw1§ lod ϭ 3.4 24% Body weight X Xp11-q26 223 C57BL/6J Bw2§ lod ϭ 6.6 (3 QTLs together) X Xq11-q13 Bw3 lod ϭ 4.3 X Xp22-q27 Mouse JU/CBA ϫ CFLP QbwX lod ϭ 24.4 17 to 20% 10-week X Xq26.3-q27.2 224 (P6 line) weight Mouse Du6 ϫ DuK Qbw1 lod ϭ 2.7 6.9% Abdominal fat 3 1p22-p21 225 4q23-q25 Qbw2 lod ϭ 7.6 17% Body mass 11 17q12-q22 Mouse Du6 ϫ Duk Bw4 F ϭ 4.79 23.1% Body weight 11 17p13-q23 226 Afw1/Afp1 F ϭ 4.89 10 to 13% Abdominal fat 4 1p36-q33 9p21-p13 Afw2 F ϭ 4.79 8.3% Abdominal fat 11 2p23-p12 5q21-q34 7p13-p12 16p13 22q12 Afw3 F ϭ 4.70 7.7% Abdominal fat 13 1q41-q43 7p15-p13 Afp2 F ϭ 4.89 8.3% Abdominal fat (%) 3 1p36-q31 3q21-q27 4q21-q32 Mouse 129/Sv ϫ Le/Suz Obq1 lod ϭ 8.0 12.3% Adiposity 7 19q13.2-q13.3 227 Obq2 lod ϭ 5.5 6.3% Adiposity 1q21-q23 2q35-q36.1 Mouse AKR/J ϫ C57L/J Obq3 lod ϭ 5.1 7.0% Adiposity 2 2q23-q31 228 9q32-q34 11p12-p11 15q13-q14 20pter-p11 20q11 Obq4 lod ϭ 4.6 6.1% Adiposity 17 6q25-q27 Mouse KK/H1Lt ϫ C57BL/6J Obq5 lod ϭ 6.3 17% Adiposity (females) 9 11q22-q24 229 Obq6 lod ϭ 5.0 11.7% Adiposity (males) X Xq26-q28 KK7 lod ϭ 6.9/4.4 Body weight/inguinal fat 7 11q21 Mouse KK-A(y) ϫ C57BL/6J Bwq1 lod ϭ 3.1 15% Body weight 4 N/A 230 Bwq2 lod ϭ 3.4/4.1 19% Body weight/26% 6 3p25 adiposity 12p13 6p21
140 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 4. Continued
Chromosomes
Crosses QTL Statistics Phenotypes Animal Human References Mouse TSOD ϫ BALB/cA Nidd5 lod ϭ 5.91 10.9% Body weight 2 2q23-q37 231 Nidd6 lod ϭ 4.65 9.2% Body weight 1 1q25-q41 Mouse M16i ϫ CAST/Ei Pfat1 N/A Adiposity 2 2p13-q21 232 15q11-qter 20pter-p11 Pfat2 N/A Adiposity 2 20qcen-q11 Pfat3 N/A Adiposity 13 5q11-q14 5q33-qter 6p23 9q21-q22 Pfat4 N/A Adiposity 15 5p14-p12 8q22-q24 Pfat5 N/A Adiposity 15 8q21-qter 22q12-qter Mouse MH ϫ C57BL/6J Hlq1 lod ϭ 5.6 4.7% Heat loss 1 1q21-q41 233 Hlq2 lod ϭ 3.7 3.1% Heat loss 2 11p14-p11 5q11-q21 Hlq3/4 lod ϭ 3.8/4.7 3.1/3.9% Heat loss 3 1p21-p13 3q21-q26 Hlq5 lod ϭ 4.06 3.4% Heat loss 7 4q28-q31 10q24-q26 11q13-q14 Fatq1 lod ϭ 8.0 5.9% Gonadal fat 1 16p13-p11 Batq1 lod ϭ 4.0 3.3% Brown fat 1 18q21.3-q22.1 Batq2 lod ϭ 3.5 2.8% Brown fat 3 1q41-q42.1 4q28-q31 Mouse DBA/2J ϫ C57BL/6J Bw6a lod ϭ 3.3 3% 6-week weight 1 1q31-q33 234 Bw6b lod ϭ 3.3 4% 6-week weight 4 9p24-p23 Bw6c lod ϭ 3.2 4% 6-week weight 5 4q12-q13 Bw6d lod ϭ 4.3 5% 6-week weight 5 12q24 Bw6e lod ϭ 4.0 4% 6-week weight 6 2p12 Bw6f lod ϭ 6.9 9% 6-week weight 7 15q11-q13 19q13 Bw6g lod ϭ 4.4 5% 6-week weight 9 6q12-q16 Bw6h lod ϭ 5.7 6% 6-week weight 11 17p13 Bw6i lod ϭ 4.1 4% 6-week weight 13 15q23-q25 Bw6j lod ϭ 3.0 3% 6-week weight 14 3p21 10q22-q24 13q14-q22 21pter-qter Bw6k lod ϭ 4.9 7% 6-week weight 17 6p21 Mouse DBA/2J ϫ C57BL/6J Pfatp4 lod ϭ 5.0 20% Predicted fat 4 9p24 235 Pfatp6 lod ϭ 4.9 (4 QTLs together) 6 3p14.1-p12 Pfatp13 lod ϭ 5.3 13 5q22-q31 Pfatp15 lod ϭ 8.6 15 8q24-qter Mouse Quackenbush-Swiss ϫ Qsbw p Ͻ 0.009 40% Body weight 10 12q22-q23 236 C57BL/6J Mouse LG/J ϫ SM/J Qlw1 lod ϭ 2.3 1.9% Late weight gain 1 2q11-q12 36,37 6p12-p11 Qlw2 lod ϭ 2.9 2.6% Late weight gain 2 20p11 20q11 Qlw3 lod ϭ 2.3 8.4% Late weight gain 3 3q25-q26 Qlw4 lod ϭ 2.4r 2.4% Late weight gain 4 6q16 8q11-q12
OBESITY RESEARCH Vol. 9 No. 2 February 2001 141 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 4. Continued
Chromosomes
Crosses QTL Statistics Phenotypes Animal Human References Qlw5 lod ϭ 2.8r 3.4% Late weight gain 6 3p26-p24 Qlw7 lod ϭ 2.0r 2.0% Late weight gain 7 15q26 Qlw9 lod ϭ 2.5r 2.4% Late weight gain 9 11q21 19p13 Qlw10 lod ϭ 2.3r 1.9% Late weight gain 10 17q22-q24 Qlw11 lod ϭ 2.6 2.4% Late weight gain 11 22q12 Qlw12 lod ϭ 2.3 2.4% Late weight gain 12 2p24-p23 Qlw13 lod ϭ 2.4 4.4% Late weight gain 13 1pter-q42 Qlw14 lod ϭ 3.1 2.9% Late weight gain 14 8p23 13q12 Qlw18 lod ϭ 1.6 3.0% Late weight gain 18 5q31-q33 Mouse NSY ϫ C3H/He Nidd3nsy lod ϭ 6.8 Epididimal fat 6 12p 237 2p13-p12 3q21 17q23 Mouse F ϫ L Fob1 lod Ͼ 3.3 4.9% 14-weeks % fat 2 2q22-qter 35 3p21.3 7q21-q22 11p13-p11 11q11-q12 Fob2 lod Ͼ 3.3 19.5% 14-weeks % fat 12 7p22-q22 (female) 14q12-q13 Fob3 lod ϭ 11.3 14.4% 14-weeks % fat 15 8q22-q24 22q12-q13 Fob4 lod Ͼ 3.3 7.3% 14-weeks % fat X Xp22-p21 Xq11-q28 8p12-p11 Rat Leprfa/Leprfa 13M ϫ Qfa1 lod ϭ 2.3 5.4% Weight (male) 1 16q13 238 WKY lod ϭ 2.5 5.8% BMI (male) 16p11 lod ϭ 2.2 6.9% BMI (female) 11p15 11q13 Qfa12 lod ϭ 2.7 7.8% Weight (female) 12 7q22 lod ϭ 3.0 8.3% BMI (female) Rat GK ϫ BN Nidd/gk1 N/A 13% Adiposity 1 3p21 239 Nidd/gk5 N/A 9% Body weight 8 11q22-q23 Nidd/gk6 N/A 7% Body weight 17 1q41-q44 bw/gk1 N/A 24% Body weight 7 8q21-q24 22q12-q13 Rat GK ϫ F Niddm1 lod ϭ 3.2 23.5% Body weight 1 10q24-q26 240 Niddm3 lod ϭ 3.0 N/A 10 17pter-q23 Weight1 lod ϭ 6.2 N/A 7 12q22-q23 Rat OLETF ϫ BN Dmo1 lod ϭ 6.0 11.6% Body weight 1 10q23-q24 40 Rat (OLETF ϫ BN) ϫ Dmo1 lod ϭ 8.2–14.0 Adipose index, fat weight, 1 10q23-q24 41 OLETF body weight Dmo4 lod ϭ 4.4–5.5 Fat weight, adipose index 1 11p15.5-p15.4 Dmo5 lod ϭ 3.5–3.6 Fat weight, adipose index 3 19p13.2-q13.3 Dmo6p lod ϭ 3.5–3.6 Fat weight, adipose index 6 14q32 Dmo7p lod ϭ 4.9–5.4 Fat weight, adipose index 7 12q22-q23 Dmo9 lod ϭ 3.5 Adipose index 11 3q26.1-q28 Dmo10 lod ϭ 3.5–3.6 Fat weight, body 11 21q22.1 weight 22q11.2 Rat Dahl ϫ MNS DAHL3 p Ͻ 0.00003 13% Body weight 3 10q25 241
142 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 4. Continued
Chromosomes
Crosses QTL Statistics Phenotypes Animal Human References Rat SHR ϫ BB/OK SHR1 lod ϭ 3.3 32% Body weight (males) 1 11p15.5 242 SHR4 lod ϭ 3.1 14% Body weight 4 7p15.3 (females) Rat WOKW ϫ DA/K Wokw1 lod ϭ 4.9 31% 30-week body 1 3p21 38 weight 10q24-q26 Wokw2 lod ϭ 4.5 16% BMI 5 1p36-p31 Pig European wild boar ϫ FAT1 N/A N/A 4 1q21-q25 243 Large white F ϭ 15.8/18.6 Back/abdominal fat 244 p Ͻ 0.0001 15.4% Visceral fat 245 p Ͻ 0.0001 7.3% Subcutaneous fat p Ͻ 0.0001 9.7% Body fat (%) Pig Wild Boar ϫ Large IGF2q F ϭ 7.1 10.4% Back fat depth 2p 11p15.5 246,247 white Pig Meishan ϫ Large BFM4 N/A Midback fat depth 4 1q21-q25 248 white Pig Meishan ϫ Duroc, Pig QTL2 p Ͻ 0.01, Average back fat 7 6p21 44,249 Hampshire, F ϭ 7.9 Landrace Minghu ϫ Hampshire, PIT1 F ϭ 3.34 42-day weight 13 3p11 45 Landrace Pig Meishan ϫ (Dutch SSC2 F ϭ 2.7r Back fat thickness 2 11p15 250 Landrace ϫ Large SSC7 F ϭ 18.0r Back fat thickness 7 6p21.3 251 white) 15q22-qter Pig Meishan ϫ Dutch SSC2 F ϭ 24.1 Back fat thickness (p) 2 11p15 43 SSC6p F ϭ 14.5 Intramuscular fat (m) 6p 16q22-qter SSC6q F ϭ 14.7 Intramuscular fat (p) 6q 1p33-p32 1p22 18p11.2 SSC7 F ϭ 30.3/49.4 Back fat thickness (p/m) 7 6p22-p21.3 Pig Meishan ϫ Dutch SSCX F ϭ 22.6 1.0 to 1.5% Back fat X Xq11.2-q22 42 thickness F ϭ 12.8 0.1 to 0.2% Intramuscular fat Pig Meishan ϫ White SSC1 F ϭ 15.4 Back fat thickness 1 9q32-q34.1 252 composite SSC7 F ϭ 14.7 Back fat thickness 7 6p21.3 SSCX F ϭ 32.3 Back fat thickness X X Chicken White Plymouth Rock AFIFA1 2.8 Food intake 1 N/A 253 ϫ White Plymouth Rock r, replicated; Mob, multigenic obesity; Dob, dietary obese; Afw, abdominal fat weight; Afp, abdominal fat percent; Bl, body length; Bw, body weight; Obq, obesity QTL; Pfat, polygenic fatness; Qlw, QTL late weight gain (6–10 weeks); Qbw, QTL body weight; Qlep, QTL for leptin; Bw6, body weight at 6 weeks; Qfa, QTL LEPRfa; Nidd/gk, type 2 diabetes/Goto–Kakizaki; bw/gk, body weight/Goto–Kakizaki; Niddm, type 2 DM; Hlq, heat loss QTL; Fatq, fat QTL; Batq, brown adipose tissue QTL; Pfatp, predicted fat percentage; Dmo, diabetic mouse; Fob, fat obesity; Wokw, Wistar Ottawa Karlsburg Rt1uW; SHR, salt hypertensive rat; SSC, swine chromosome; AFIFA, avian feed intake at a fixed age interval. p, paternal effect; m, maternal effect; N/A, not available. * Synteny relationships established according to the following references: 84–88. † Also observed in the cross CAST/Ei ϫ C57BL/6J (179). ‡ Also observed in the CAST/Ei ϫ C57BL/6J F2 intercross (193). § Also observed in the cross (C3H/He ϫ A/J) ϫ Mus spretus (65). Status as of October 2000.
OBESITY RESEARCH Vol. 9 No. 2 February 2001 143 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 5. Evidence for the presence of an association between markers of candidate genes with BMI, body fat, and other obesity-related phenotypes
Gene Location N (cases) Phenotype p value References TNFRSF1B 1p36.3-p36.2 217 BMI, leptin Ͻ0.05 52 LEPR 1p31 20 % Fat 0.003 254 308 FFM in subjects with BMI Ն 27 0.03 to 0.05 255 130 Extreme obesity in children 0.02 to 0.04 256 502 BMI, FM 0.005 to 0.03 53 267 BMI, abdominal sagittal diameter 0.041 and 0.046 54 HSD3B1 1p13.1 132 12-year changes in ⌺6 skinfolds 0.04 257 LMNA 1q21.2-q21.3 48 Leptin, leptin to BMI ratio in partial Ͻ0.05 86 lipodystrophy families 306 BMI, WHR, leptin in Canadian Oji-Cree Ͻ0.05 55 47 Familial partial lipodystrophy Ͻ0.0001 89 ATP1A2 1q21-q23 122 % Fat, RQ Ͻ0.05 258 156 RQ in young adults 0.0001 259 AGT 1q42-q43 316 WHR 0.007 260 94 FM in women Ն 42 years 0.008 to 0.02 261 ACP1 2p25 75 BMI in children 0.02 262 265 BMI in type 2 DM subjects 0.002 263 APOB 2p24-p23 232 BMI 0.005 264 181 BMI 0.05 265 56 % Fat, abdominal fat 0.04 266 POMC 2p23.3 337 Leptin in Mexican Americans 0.001 267 ADRA2B 2p13-q13 166 BMR in obese nondiabetics 0.01 268 IRS1 2q36 1748 Current BMI and ⌬BMI since age 25 in 0.04 to 0.05 269 African Americans 156 Leptin in obese subjects 0.03 270 PPARG 3p25 820 Leptin in obese subjects 0.001 271 333 BMI in middle-aged subjects 0.03 272 973 BMI in elderly subjects 0.02 752 ⌬BMI in obese men 0.002 to 0.008 273 869 ⌬BMI in lean men 121 BMI 0.03 274 141 BW, BMI, LBM, fat mass, waist and hip 0.002 to 0.05 275 girths 375 Severe obesity with early onset Ͻ0.05 58 921 BMI, waist girth, leptin in Mexican 0.015 to 0.028 57 Americans 838 BW, height, BMI, waist girth 0.002 to 0.04 56 APOD 3q26.2-qter 114 BMI 0.006 276 CCKAR 4p15.2-p15.1 1296 % Fat, leptin 0.003 to 0.041 81 FABP2 4q28-q31 395 Abdominal fat 0.008 277 507 BMI, % fat 0.01 278 UCP1 4q28-q31 123 High fat gainers over 12 years 0.05 279 163 Weight and BMI loss Ͻ0.05 280 113 Weight loss in Japanese women 0.001 281
144 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 5. Continued
Gene Location N (cases) Phenotype p value References 526 BMI in overweight women 0.02 59 NPY5R 4q31-q32 74 Obesity (BMI 40–47 kg/m2) in Pima Ͻ0.05 64 Indians CART 5q 612 WHR in men 0.0021 84 GRL 5q31-q32 51 Abdominal visceral fat in lean subjects 0.003 Ͻ p Ͻ 0.007 282 262 BMI, WHR, abdominal sagittal diameter, 0.001 to 0.039 65 leptin ADRB2 5q31-q32 140 BMI, fat mass, fat cell volume 0.001 Ͻ p Ͻ 0.009 283 508 BMI in Japanese subjects 0.001 284 836 Body weight, BMI, waist circumference, Ͻ0.002 285 hip circumference, WHR in sedentary French men 574 BMI in Japanese subjects 0.009 to 0.003 286 277 BMI in Japanese men 0.004 287 826 Obesity, BMI, waist circumference, hip 0.05 to 0.01 67 circumference, WHR 224 BMI Ͼ 35 kg/m2 in men 0.01 66 180 BMI 0.003 to 0.02 68 284 Leptin 0.033 87 TNFA 6p21.3 38 % Fat 0.02 288 363 BMI 0.01 289 1351 BMI 0.004 290 110 Obesity (27 Ͻ BMI Ͻ 35 kg/m2) 0.02 71 378 BMI, % fat in women 0.02 72 1047 Obesity 0.035 291 GCK 7p15.3-p15.1 58 Birth weight in boys only 0.002 292 NPY 7p15.1 369 Birth weight 0.03 82 595 BMI, WHR 0.03 to 0.04 73 PON2 7q21.3 100 Birth weight in Trinidadian neonates of Ͻ0.05 293 South Asian origin LEP D7S2519, 7q31.3 168 Weight loss 0.006 Ͻ p Ͻ 0.007 294 649, 530, 1875 84 Body weight 0.05 295 395 Leptin 0.02 296 117 Leptin 0.04 297 Leptin response to diet 0.005 103 BMI, body weight Ͻ0.05 298 211 Severe obesity in women 0.017 to 0.035 74 LPL 8p22 236 BMI (leanness) 0.05 299 ADRB3 8p12-p11.2 128 Weight gain over 25 years 0.01 300 185 Weight gain over 20 years, current 0.007 Ͻ p Ͻ 0.03 301 weight 335 WHR in women 0.02 302 350 BMI 0.009 303 49 BMI 0.03 304
OBESITY RESEARCH Vol. 9 No. 2 February 2001 145 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 5. Continued
Gene Location N (cases) Phenotype p value References 295 BMI Ͻ0.05 305 254 Early onset obesity 0.002 306 131 Abdominal visceral fat, fat mass Ͻ0.01 307 398 Visceral/subcutaneous abdominal fat, 0.02 Ͻ p Ͻ 0.03 308 BMI 83 BMI in CAD patients Ͻ0.05 309 53 Obesity Ͻ0.05 310 586 BMI and hip circumference in women Ͻ0.03 311 56 BMI, fat mass, waist circumference Ͻ0.05 312 261 BMI Ͻ0.05 313 211 Moderate obesity 0.02 314 179 ⌬BMI during pregnancy 0.006 to 0.02 315 76 FM in Thai males Ͻ0.05 316 553 Obesity in Japanese children 0.02 70 213 Total and subcutaneous abdominal fat 0.018 and 0.029 66 802 BMI 0.021 69 CBFA2T1 8q22 281 % fat, BMI, waist and hip circumference 0.0002 Ͻ p Ͻ 0.02 317 ADRA2A 10q24-q26 72 TER in women 0.002 318 476 Total and subcutaneous abdominal fat 0.012 and 0.003 66 SUR1 11p15.1 232 Morbid obesity 0.02 319 IGF2 11p15.5 1474 BMI 0.02 320 INS 11p15.5 758 Birth weight 0.009 321 52 WHR in obese women 0.005 322 1152 BMI Ͻ0.0002 75 UCP2 11q13 82 Sleeping and 24-hour metabolic rate 0.007 Ͻ p Ͻ 0.04 323 790 BMI in subjects Ͼ45 years 0.04 220 BMI in South Indian women 0.02 324 143 BMI in South Indian parents of type 2 Ͻ0.001 DM probands 60 24-hour EE, 24-hour SPA, sleeping SPA, 0.005 to 0.05 325 24-hour nonprotein RQ, 24-hour fat oxidation 105 BW, BMI, % overweight, % fat, FM, 4 0.001 to 0.05 60 skinfolds and their sum 813 Obesity (BMI Ͼ 30 kg/m2) 0.002 62 41 BW and FM gain in peritoneal dialysis Ͻ0.05 61 patients UCP3 11q13 120 BMI, RQ, NPRQ, FATOX/LBM in 0.008 to 0.04 326 African Americans 382 Current BMI, maximal BMI and BW 0.02 to 0.04 327 during diet therapy in morbidly obese patients 401 BMI in morbidly obese subjects 0.0037 63 APOA4 11q23 375 BMI and WHR in young men without 0.004 328 family history of MI
146 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 5. Continued
Gene Location N (cases) Phenotype p value References 613 BMI, % fat 0.004 to 0.023 76 DRD2 11q22.2-q22.3 392 Relative weight 0.002 329 383 Iliac and triceps skinfold 0.002 to 0.039 85 176 Obesity (BMI Ͼ 30 kg/m2) 0.002 to 0.003 77 GNB3 12p13 197 BMI in hypertensives 0.02 330 1950 Body weight and BMI in young white, 0.001 to 0.05 331 Chinese, and black African males 213 BMI, waist and hip girths and skinfolds Ͻ0.05 332 in Nunavut Inuit 230 BMI in primiparous women 0.01 78 181 Babies’ birth weight (mothers’ genotype) 0.015 83 IGF1 12q22-q23 502 FM, % Fat, FFM, Ͻ0.05 333 ⌬FFM after 20-week endurance training 0.005 CD36L1 12q24.1-q24.3 288 BMI in healthy lean women 0.004 to 0.03 334 HTR2A 13q14-q21 276 Dietary energy and carbohydrate and 0.028 to 0.047 88 alcohol intake in obese subjects MC5R 18p11.2 156 BMI in females 0.003 335 MC4R 18q22 156 FM, % fat, FFM in females 0.002 Ͻ p Ͻ 0.004 335 INSR 19p13.3-p.13.2 75 Obesity (BMI Ͼ 26) in hypertensives 0.05 336 LDLR 19p13.3 84 BMI in hypertensives 0.004 337 112 BMI in hypertensives 0.04 338 83 BMI in normotensives 0.008 339 270 Obesity (BMI Ն 26) 0.02 340 131 BMI, triceps and subscapular skinfold, 0.001 to 0.021 79 arm fat index LIPE 19q13.1-q13.2 380 Obesity 0.002 341 GYS1 19q13.3 130 Obesity 0.03 342 ADA 20q12-q13.11 273 BMI in type 2 DM subjects 0.0004 to 0.01 343 HTR2C Xq24 589 BMI Ͼ 28 kg/m2 0.009 to 0.02 80
Status as of October 2000. FFM, fat-free mass; WHR, waist-to-hip ratio; RQ, respiratory quotient; TER, trunk-to-extremity skinfolds ratio; BMR, basal metabolic rate; DM, diabetes mellitus; LBM, lean body mass; CAD, coronary artery disease; BW, body weight; NPRQ, non-protein respiratory quotient; FATOX/LBM, fat oxidation adjusted for lean body mass; EE, energy expenditure; SPA, spontaneous physical activity; FM, fat mass. the past year have shown significant associations of BMI, body (83) genes have been reported to be associated with birth weight, and obesity with polymorphisms in TNFRS1B (52), weight. Abdominal obesity phenotypes (abdominal visceral LEPR (53,54), LMNA (55), peroxisome proliferator activated and subcutaneous fat, waist girth, waist-to-hip ratio, and ab- receptor, gamma (PPARG) (56–58), UCP1 (59), UCP2 (60– dominal sagittal diameter) showed associations with LEPR 62), UCP3 (63), NPY5R (64), GRL (65), ADRB2 (66–68), (54), LMNA (55), PPARG (56,57), CART (84), GRL (65), ADRB3 (69,70), tumor necrosis factor, alpha (TNFA) (71,72), ADRB2 (67), NPY (73), ADRB3 (66), and ADRA2A (66) NPY (73), LEP (74), INS (75), APOA4 (76), DRD2 (77), markers. Polymorphisms in the UCP2 (60), DRD2 (85), and GNB3 (78), MC4R (11), LDLR (79), and HTR2C (80). Fat LDLR (79) loci have been reported to be associated with mass and/or percentage of body fat was associated with mark- skinfold thickness phenotypes. Plasma leptin levels have been ers of LEPR (53), CCKAR (81), TNFA (72), UCP2 (60,61), found to be associated with DNA sequence variation in the and APOA4 (76). Polymorphisms in the NPY (82) and GNB3 TNFRS1B (52), LMNA (86), PPARG (57), CCKAR (81),
OBESITY RESEARCH Vol. 9 No. 2 February 2001 147 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 6. Evidence for the presence of linkage with obesity-related phenotypes
Gene* Markers Location N (pairs) Phenotypes p or lod value References PGD 1p36.2-p36.13 Ͼ168 Suprailiac skinfold p ϭ 0.03 344 D1S193,200,476 1p35-p31 202–251 BMI, ⌺6 skinfolds, fat 0.009 Ͻ p Ͻ 0.02 345 mass LEPR Q223R, 1p31 268–324 BMI, ⌺6 skinfolds, fat 0.005 Ͻ p Ͻ 0.05 255 CA (IVS 3), mass, fat-free mass CTTT (IVS 16) QTL D1S550 1p31-p21 236 24-hour RQ lod ϭ 2.8 346 ATP1B1 1q22-q25 94 RQ p ϭ 0.04 258 ATP1A2 1q21-q23 289 RQ p ϭ 0.02 259 ACP1 2p25 Ͼ300 BMI p ϭ 0.004 347 Ͼ168 Triceps skinfold p ϭ 0.02 344 QTL D2S1788 2p21 Ͼ5000 Relative Leptin, fat mass lod ϭ 4.9/2.8 348 pairs D2S1788 720 Subjects; 230 Leptin, BMI 0.008 Ͻ p Ͻ 0.03 349 families D2S1788 337 Individuals Leptin lod ϭ 7.5 267 QTL D2S165,367 2p22-p21 264 Leptin lod ϭ 2.4/2.7 136 IGKC 2p12 Ͼ168 Triceps skinfold p ϭ 0.03 344 QTL D3S2432 3p24.2-p22 377 % Fat lod ϭ 2.0 350 GYPA 4q28.2-q31.1 160 TER p ϭ 0.02 351 QTL D5S426 5p11 264 Leptin lod ϭ 2.9 136 ISL1 5q22.3 226 Obesity p ϭ 0.03 352 284 BMI, leptin 0.0004 Ͻ p Ͻ 0.006 GRL 5q31-q32 88 BMI Ͼ27 p ϭ 0.009 353 ADRB2 5q31-q32 66 TER p ϭ 0.02 318 BF 6p21.3 Ͼ168 Triceps, subscapular, 0.01 Ͻ p Ͻ 0.03 344 suprailiac skinfolds TNFA TNFir24, 6p21.3 Ͼ255 % Fat 0.002 Ͻ p Ͻ 0.05 289 D6S273,291 GLO1 6p21.3-p21.1 Ͼ168 Suprailiac skinfold, 0.004 Ͻ p Ͻ 0.05 344 relative weight QTL D6S271 6p21 1199 Leptin lod ϭ 2.1 113 NPY 7p15.1 545 Principal component p ϭ 0.05 354 of height, weight, skinfolds, abdominal and hip circumferences 170 Obesity p ϭ 0.04 QTL D7S1808 7p15.3 336 Fat-free mass lod ϭ 2.7 135 LEP 7q31.3 47 Body fat p ϭ 0.008 355 D7S680,514,530 60 BMI Ͼ 35 0.002 Ͻ p Ͻ 0.009 356 D7S504,1875 59 BMI Ն 40 p ϭ 0.04 357 88 BMI p ϭ 0.04 358 D7S504 46 BMI Ͼ 85th percentile p ϭ 0.001 359 D7S514,495 545 BMI, skinfolds, fat, 0.0001 Ͻ p Ͻ 0.02 360 waist circumference D7S1875 545 WHR p ϭ 0.009 354 KEL 7q33 402 BMI, ⌺6 skinfolds Ͻ0.0001 351 TER 0.04 ADRB3, D8S1121 8p12-p11.2 470 Subjects from BMI lod ϭ 3.2 361 10 large pedigrees QTL D8S1110 8q11.1 Ͼ5000 Relative pairs Leptin lod ϭ 2.2 348 ORM1 9q31-q32 Ͼ168 Suprailiac skinfold p ϭ 0.03 344 AK1 9q34.1 Ͼ168 Suprailiac skinfold p ϭ 0.01 344
148 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 6. Continued
Gene* Markers Location N (pairs) Phenotypes p or lod value References QTL D10S197 10p12.3 264 Obesity lod ϭ 4.9 136 D10S204,193,1781 10p11.22 386 Subjects from Obesity 1.1 Ͻ lod Ͻ 2.5 137 and TCF8 93 families SUR1 D11S419 11p15.1 67 BMI Ն 27 p ϭ 0.003 319 CCKBR 11p15.4 221 Leptin p ϭ 0.01 352 UCP2/UCP3 11q13 240 Relative pairs RMR p ϭ 0.000002 362 QTL D11S2000,2366 11q22 277 % Fat lod ϭ 2.8 350 D11S2366 11q22 451 % Fat lod ϭ 2.1 346 QTL D11S976 11q23 236 24-hour EE lod ϭ 2.0 346 QTL D11S912 11q24 1766 BMI lod ϭ 3.6 138 IGF1 12q22-q23 352 Visceral fat p ϭ 0.02 333 ESD 13q14.1-q14.2 194 ⌺6 skinfolds, % fat p Ͻ 0.04 351 QTL IGF1R, D15S652, 15q25-q26 336 Fat-free mass 2.0 Ͻ lod Ͻ 3.6 135 657 QTL D16S265 16q21 1199 Leptin lod ϭ 20.0 113 MC5R 18p11.2 242 to 289 BMI, ⌺6 skinfolds, fat 0.001 Ͻ p Ͻ 0.02 335 mass, % fat, fat-free mass, RMR MC4R 18q22 210 RQ p ϭ 0.04 335 105 Obesity 0.001 Ͻ p Ͻ 0.003 363 QTL D18S877,535 18q12 336 Fat-free mass lod ϭ 3.6 135 QTL D18S877 18q21 451 % Fat lod ϭ 2.3 346 QTL D18S115 18q21 193 Obesity lod ϭ 2.4 134 ADA 20q12-q13.11 428 BMI, ⌺6 skinfolds 0.02 Ͻ p Ͻ 0.001 351 ADA, 20q12-q13 139 to 226 BMI, ⌺6 skinfolds, fat 0.004 Ͻ p Ͻ 0.02 219 D20S17,120 mass, % fat MC3R 20q13.2-q13.3 212 to 258 BMI, ⌺6 skinfolds, fat 0.008 Ͻ p Ͻ 0.02 219 mass QTL D20S601 20q11.2 236 24-hour RQ lod ϭ 3.0 346 QTL D20S107,211,149 20q13 423 BMI Ͼ 30, % fat 3.0 Ͻ lod Ͻ 3.2 364 P1 22q11.2-qter Ͼ168 Relative weight p ϭ 0.03 344 QTL DXS6804 Xq24 193 Obesity lod ϭ 3.1 134
RQ, respiratory quotient; RMR, resting metabolic rate; TER, trunk-to-extremity skinfolds ratio; WHR, waist-to-hip circumferences ratio; EE, energy expenditure. * See Appendix for the complete name of the gene. The absence of a gene symbol indicates that the linkage study involved a targeted chromosomal region. QTL means human quantitative trait locus identified from a genome scan. Status as of October 2000.
GRL (65), and ADRB2 (87) markers. Finally, a HTR2A gene less weight during a weight loss program than those who polymorphism was associated with dietary energy and carbo- were homozygotes for the common allele at both loci hydrate and alcohol intake in obese subjects (88), and the (90). In a cohort of Finnish type 2 diabetics and nondi- LMNA gene was associated with familial partial lipo- abetic controls, subjects who carried a rare allele at both dystrophy (89). the ADRB3 and UCP1 loci (n ϭ 11) gained more weight Gene–gene and gene–environment interactions on obe- during a 10-year follow-up period than those who were sity-related phenotypes have also been reported. In the homozygotes for the wild-type allele (91). In a cohort of Que´bec Family Study cohort, significant interactions were morbidly obese patients, Otabe et al. (63) reported a reported between the ADRA2A and ADRB3 polymor- significant inverse association between physical activity phisms on abdominal total and subcutaneous fat (66). In level and BMI in the homozygotes for the common allele a group of obese German women, those who carried a in the UCP3 locus, whereas no association was found in rare allele in both the ADRB3 and IRS1 loci (n ϭ 6) lost other genotypes. An association between a GNB3 poly-
OBESITY RESEARCH Vol. 9 No. 2 February 2001 149 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Table 7. Evolution in the Status of the Human Obesity Gene Map
1994 1995 1996 1997 1998 1999 2000 Single-gene mutations* — — —266 6 Mendelian disorders with map location 8 12 13 16 16 20 24 Candidate genes with positive findings 9 10 13 21 29 40 48 Animal QTLs 7 9 24 55 67 98 115 Human QTLs from genome scans — — — 3 8 14 21 Other human linkages 9 9 15 17 29 37 38
* Number of genes, not number of mutations. From references 1 to 6 plus this review.
morphism and BMI that was detected in primiparous QTL was detected on chromosome 18q21, where a max- sedentary women was not observed in their physically imum likelihood score of 2.42 was obtained between active counterparts (78). obesity and D18S1155 (134). The results of a genome- In addition to the 40 new studies with positive findings, wide scan for fat-free mass assessed from underwater we found 58 studies showing no associations between obe- weighing measurements were also reported in the Quebec sity-related phenotypes and selected candidate genes. Family Study (135). In the latter study, based on 292 Among the negative studies, the most frequent ones were markers with an average intermarker distance of 11.9 cM those performed with markers of ADRB3 (six studies) and typed on a maximum of 336 sibpairs, significant (62,92–96), PPARG (seven studies) (97–103), LPL (four evidence of linkage with fat-free mass was found with studies) (94,104–106), and UCP1 (four studies) three markers (IGF1R, D15S652, and D15S657) on chro- (62,91,94,96). Other markers yielding negative findings mosome 15q25-q26. Two other chromosomal regions were related to ADRB2 (107,108), LEP (109,110), LEPR also provided evidence of linkage with fat-free mass (70,110), LIPC (111), CART (112,113), TCF1 (114,115), (FFM): one on 18q12 with D18S877 (logarithm of odds TNFA (116–118), UCP2 (119), UCP3 (120), APOA4 [lod] ϭ 3.5) and D18S535 (lod ϭ 3.6) and another on (121), DRD2 (64), DRD4 (122), VDR (123,124), ESR1 7p15.3 with D7S1808 (lod ϭ 2.7). Another genome scan (123), BRS3 (125), MC3R (126), MC4R (127), APOE for loci linked to plasma leptin concentrations was re- (128,129), HNF4A (114), IRS1 (90,114,130), HNF6 (114), ported in Pima Indians (113) based on a total of 1199 IGF1R (131), IGF1 (131), INSR (132), and adiponectin sibpairs. The strongest evidence of linkage with age- and (133). It should be noted that the majority of the studies with gender-adjusted plasma leptin concentrations was found positive findings also reported nonsignificant associations on chromosome 6p21 (lod ϭ 2.1) near the marker with other obesity-related phenotypes and/or candidate gene D6S271 at a map distance of 54 cM from the p-terminal markers. Thus, the actual number of negative findings is (113). Using the Haseman–Elston sibpair linkage considerably higher than suggested by the above list. method, the best evidence of linkage with plasma leptin was found with the marker D16S265 on chromosome 16q21 near the BBS2 locus (113). Linkage Studies In an attempt to replicate the linkage previously re- A summary of the loci that have been shown to be linked ported with obesity on chromosome 10p12 in French to obesity-related phenotypes in genome-wide scans or families (136), Hinney et al. (137) genotyped 11 markers other linkage studies is presented in Table 6. A total of 59 spanning ϳ23 cM from 10p13 to 10q11 in a sample of genes or loci have provided significant evidence of link- 386 individuals from 93 German families that had at least age with obesity-related phenotypes. Three genome-wide two obese children. The marker D10S197, which pro- scans for obesity-related phenotypes were reported since vided the strongest evidence of linkage in the French last year’s review. One of these genome-wide scans was study (136), showed a lod score of 1.7 in the German performed in 193 Finnish obese (BMI of Ն30 kg/m2) families. In the German study (137), evidence of linkage sibpairs using 374 markers with an average density of 10 to obesity was observed with markers D10S204 (lod ϭ cM (134). The strongest evidence of linkage to obesity 2.0), D10S193 (lod ϭ 1.1), TCF8 (lod ϭ 2.4), and was obtained on chromosome Xq24 with DX6804, which D10S1781 (lod ϭ 2.2), which are ϳ5 cM more centro- had a maximum likelihood score of 3.14. Another obesity meric than D10S197. These results suggest the presence
150 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Figure 1.
OBESITY RESEARCH Vol. 9 No. 2 February 2001 151 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al.
Figure 1. The 2000 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 website hosted by the National Center for Biotechnology Information, National Institutes of Health (Bethesda, MD) (http//www.ncbi.nlm.nih.gov/). The chro- mosome 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 animal QTLs are given in Table 4.
of an obesity QTL on chromosome 10p11.2 near the Finally, a linkage exclusion analysis of the chromosomal centromere. To determine whether genetic variation in region 11q13 containing the UCP2 and UCP3 genes, the DRD2 gene locus could be responsible for the linkage performed in 458 individuals from 10 randomly ascer- reported with BMI on 11q24 after a genomic scan in tained Mexican American families, revealed that genetic Pima Indians (138), a total of 1187 Pima Indians were variation around the UCP2 and UCP3 genes was unlikely genotyped for two polymorphisms within the DRD2 gene to exert an influence on BMI, fat mass, waist circumfer- (64). The effect of the DRD2 polymorphisms on the ence, and plasma leptin levels (139). 11q24 linkage signal was evaluated by repeating the chromosome 11 linkage analyses and comparing the lod scores obtained from a model that included the DRD2 Conclusions genotypes with the lod scores obtained from a model that Figure 1 depicts the human obesity gene map and incor- did not include these genotypes. The results of these porates the loci from single-gene mutation rodent models of linkage analyses were the same regardless of whether or obesity, human obesity cases due to single-gene mutations, not the DRD2 genotypes were included (64), suggesting QTLs from crossbreeding experiments and genome-wide that the DRD2 polymorphisms are not responsible for the scans, all relevant Mendelian disorders that have been linkage of BMI to chromosome 11q24 in Pima Indians. mapped to a chromosomal region, and genes or markers that
152 OBESITY RESEARCH Vol. 9 No. 2 February 2001 The Human Obesity Gene Map: The 2000 Update, Pe´ russe et al. have been shown to be associated or linked with an obesity 8. Holder JL Jr, Butte NF, Zinn AR. Profound obesity asso- phenotype. The map reveals that putative loci affecting ciated with a balanced translocation that disrupts the SIM1 obesity-related phenotypes are found on all but chromo- gene. Hum Mol Genet. 2000;9:101–8. some Y of the human chromosomes. 9. Hinney A, Schmidt A, Nottebom K, et al. Several muta- The number of genes and other markers associated or tions in the melanocortin-4 receptor gene including a non- linked with human obesity phenotypes continues to expand. sense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab. 1999; The progress made over the last decade is exemplified by 84:1483–6. the numbers collated in Table 7. It is obvious that the human 10. Sina M, Hinney A, Ziegler A, et al. Phenotypes in three obesity gene map has become significantly more detailed pedigrees with autosomal dominant obesity caused by hap- and complex since the first version developed in 1994. Of loinsufficiency mutations in the melanocortin-4 receptor course, some of these loci will turn out to be more important gene. Am J Hum Genet. 1999;65:1501–7. than others, and many will eventually be proven to be false 11. Vaisse C, Clement K, Durand E, Hercber S, Guy-Grand positive. The main task, including the identification or the B, Froguel P. Melanocortin-4 receptor mutations are a fre- positional cloning of the QTL genes, remains to identify the quent and heterogeneous cause of morbid obesity. J Clin combination of genes and mutations that are contributing Invest. 2000;106:253–62. most to human obesity and to define under which environ- 12. Wajnrajch MP, Gertner JM, Harbison MD, Chua SC mental circumstances. It is also likely that the topic of Jr, Leibel RL. Nonsense mutation in the human growth gene–gene interactions will receive more attention in the hormone-releasing hormone receptor causes growth fail- coming years. ure analogous to the little (lit) mouse. Nat Genet. 1996; 12:88–90. 13. Salvatori R, Hayashida CY, Aguiar-Oliveira MH, et al. Acknowledgments Familial dwarfism due to a novel mutation of the growth The research of the authors on the genetics of obesity is hormone-releasing hormone receptor gene. J Clin Endocri- funded by the Medical Research Council of Canada (Grants nol Metab. 1999;84:917–23. MT-13960 and GR-15187). C.B. is supported by the George 14. Rosenbloom AL, Almonte AS, Brown MR, Fisher DA, A. Bray Chair in Nutrition. We thank Diane Drolet for her Baumbach L, Parkes JS. Clinical and biochemical pheno- dedicated contribution to the compendium and the develop- type of familial anterior hypopituitarism from mutation of the ment of the manuscript. The list of genes and markers PROP1 gene. J Clin Endocrinol Metab. 1999;84:50–7. 15. Mendonca BB, Osorio MG, Latronico AC, Estefan V, Lo currently in the map as well as the pictorial representation of LS, Arnhold IJ. Longitudinal hormonal and pituitary imag- the map is also available on the website of the Donald B. ing changes in two females with combined pituitary hormone Brown Research Chair on Obesity at the following address: deficiency due to deletion of A301,G302 in the PROP1 gene. http://www.obesity.chair.ulaval.ca/genes.html and on the web- J Clin Endocrinol Metab. 1999;84:942–5. site of the Pennington Biomedical Research Center Human 16. Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in Genomics Laboratory at: http://www.eureka.pbrc.edu. Canadian kindreds with Dunnigan-type familial partial lipo- dystrophy. Hum Mol Genet. 2000;9:109–12. References 17. Aldred MA, Trembath RC. Activating and inactivating 1. Pe´russe L, Bouchard C. Identification of genes contributing mutations in the human GNAS1 gene. 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Worldwide ethnic and insulin levels in the Quebec Family Study. Obes Res. distribution of the G protein 3 subunit 825T allele and 1997;5:115–21. its association with obesity in Caucasian, Chinese, and 346. Norman R, Tataranni P, Pratley R, et al. Autosomal Black African individuals. J Am Soc Nephrol. 1999;10: genomic scan for loci linked to obesity and energy me- 1921–30. tabolism in Pima Indians. Am J Hum Genet. 1998;62:659– 332. Hegele RA, Anderson C, Young TK, Connelly PW. 68. G-protein 3 subunit gene splice variant and body fat 347. Bailey-Wilson JE, Wilson AF, Bamba V. Linkage analysis distribution in Nunavut Inuit. Genome Res. 1999;9:972–7. in a large pedigree ascertained due to essential familial 333. Sun G, Gagnon J, Chagnon Y, et al. Association and hypercholesterolemia. Genet Epidemiol. 1993;10:665–9. linkage between an insulin-like growth factor-1 gene poly- 348. Comuzzie AG, Hixson JE, Almasy L, et al. A major morphism and fat free mass in the HERITAGE family study. quantitative trait locus determining serum leptin levels and Int J Obes Relat Metab Disord. 1999;23:929–35. fat mass is located on human chromosome 2. Nat Genet. 334. Acton S, Osgood D, Donoghue M, et al. Association of 1997;15:273–6. polymorphisms at the SR-BI gene locus with plasma lipid 349. Rotimi CN, Comuzzie AG, Lowe WL, Luke A, Blangero levels and body mass index in a white population. Arterio- J, Cooper RS. The quantitative trait locus on chromosome 2 scler Thromb Vasc Biol. 1999;19:1734–43. for serum leptin levels is confirmed in African-Americans. 335. Chagnon YC, Chen WJ, Pe´russe L, et al. Linkage and Diabetes. 1999;48:643–4. association studies between the melanocortin receptors 4 and 5 genes and obesity-related phenotypes in the Que´bec Family 350. Norman RA, Thompson DB, Foroud T, et al. Genome- Study. Mol Med. 1997;3:663–73. wide search for genes influencing percent body fat in Pima 336. Zee RYL, Lou YK, Morris BJ. Insertion variant in intron 9, Indians: suggestive linkage at chromosome 11q21–q22. but not microsatellite in intron 2, of the insulin receptor gene Am J Hum Genet. 1997;60:166–73. is associated with essential hypertension. J Hypertens. 1994; 351. Borecki IB, Rice T, Pe´russe L, Bouchard C, Rao DC. An 12:S13–22. exploratory investigation of genetic linkage with obesity 337. Zee RYL, Griffiths LR, Morris BJ. Marked association of phenotypes: the Quebec Family Study. Obes Res. 1994;2: a RFLP for the low density lipoprotein receptor gene with 213–9. obesity in essential hypertensives. Biochem Biophys Res 352. Cle´ment K, Dina C, Basdevant A, et al. A sib-pair analysis Commun. 1992;189:965–71. study of 15 candidate genes in French families with morbid 338. Zee RYL, Schrader AP, Robinson BG, Griffiths LR, obesity: indication for linkage with islet 1 locus on chromo- Morris BJ. Association of HincII RFLP of low density some 5q. Diabetes. 1999;48:398–402.
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353. Cle´ment K, Philippi A, Jury C, et al. Candidate gene 359. Onions K, Hunt S, Rutkowski M, et al. Genetic markers at the approach of familial morbid-obesity: linkage analysis of the leptin (OB) locus are not significantly linked to hypertension in glucocorticoid receptor gene. Int J Obes Relat Metab Disord. African Americans. Hypertension. 1998;31:1230–4. 1996;20:507–12. 360. Duggirala R, Stern MP, Mitchell BD, et al. Quantitative 354. Bray MS, Boerwinkle E, Hanis CL. Linkage analysis of candi- variation in obesity-related traits and insulin precursors date obesity genes among the Mexican-American population of linked to the OB gene region on human chromosome 7. Am J Starr County, Texas. Genet Epidemiol. 1999;16:397–411. Hum Genet. 1996;59:694–703. 355. Lapsys NM, Furler SM, Moore KR, et al. Relationship 361. Mitchell B, Cole S, Comuzzie A, et al. A quantitative trait of a novel polymorphic marker near the human obese locus influencing BMI maps to the region of the -3 adren- (OB) gene to fat mass in healthy women. Obes Res. ergic receptor. Diabetes. 1999;48:1863–7. 1997;5:430–3. 362. Bouchard C, Pe´russe L, Chagnon YC, Warden C, Ric- 356. Cle´ment K, Garner C, Hager J, et al. Indication for linkage quier D. Linkage between markers in the vicinity of the of the human OB gene region with extreme obesity. Diabe- uncoupling protein 2 gene and resting metabolic rate in tes. 1996;45:687–90. humans. Hum Mol Genet. 1997;6:1887–9. 357. Reed DR, Ding Y, Xu W, Cather C, Green ED, Price RA. 363. Ohman M, Oksanen L, Kainulainen K, et al. Testing of Extreme obesity may be linked to markers flanking the human homologues of murine obesity genes as candidate human OB gene. Diabetes. 1996;45:691–4. regions in Finnish obese sib pairs. Eur J Hum Genet. 1999; 358. Roth H, Hinney A, Ziegler A, et al. Further support for 7:117–24. linkage of extreme obesity to the obese gene in a study group 364. Lee JH, Reed DR, Li WD, et al. Genome scan for human of obese children and adolescents. Exp Clin Endocrinol obesity and linkage to markers in 20q13. Am J Hum Genet. Diabetes. 1997;105:341–4. 1999;64:196–209.
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APPENDIX: Symbols, full names, and cytogenetic location of genes and loci of the 2000 human obesity gene map*
Gene or locus Name Location A
ACH Achondroplasia 4p16.3 ACP1 Acid phosphatase 1, soluble 2p25 ADA Adenosine deaminase 20q12-q13.11  ADRB2 Adrenergic, 2-, receptor, surface 5q31-q32 ␣ ADRA2A Adrenergic, 2A-, receptor 10q24-q26 ␣ ADRA2B Adrenergic, 2B-, receptor 2p13-q13  ADRB3 Adrenergic, 3-, receptor 8p12-p11.2 AGS Angelman syndrome with obesity 15q11-q13 AGT Angiotensinogen 1q42-q43 AHO Albright hereditary osteodystrophy 20q13.2 AHO2 Albright hereditary osteodystrophy 2 15q AK1 Adenylate kinase 1 9q34.1 ALMS1 Alstrom syndrome 1 2p13-p12 APOA4 Apolipoprotein A-IV 11q23 APOB Apolipoprotein B (including antigen ϫ antigen) 2p24-p23 APOD Apolipoprotein D 3q26.2-qter APOE† Apolipoprotein E 19q13.2 ASIP Agouti (mouse)-signaling protein 20q11.2-q12 ATP1A2 ATPase, Naϩ/Kϩ transporting, ␣2(ϩ) polypeptide 1q21-q23 ATP1B1 ATPase, Naϩ/Kϩ transporting, 1 polypeptide 1q22-q25 ATRN Attractin (with dipeptidylpeptidase IV activity) 20p13
B, C
BBS1 Bardet–Biedl syndrome 1 11q13 BBS2 Bardet–Biedl syndrome 2 16q21 BBS3 Bardet–Biedl syndrome 3 3p13-p12 BBS4 Bardet–Biedl syndrome 4 15q22.3-q23 BBS5 Bardet–Biedl syndrome 5 2q31 BBS6 Bardet–Biedl syndrome 6 20p12 BF B-factor, properdin 6p21.3 BFLS Borjeson–Forssman–Lehman syndrome Xq26.3 BRS3† Bombesin-like receptor 3 Xq26-q28 BSCL Berardinelli–Seip congenital lipodystrophy 9q34 CART Cocaine- and amphetamine-regulated transcript 5q CBFA2T1 Core-binding factor, runt domain, ␣ subunit 2; translocated to, 1; cyclin 8q22 D-related CCKAR Cholecystokinin A receptor 4p15.2-p15.1 CCKBR Cholecystokinin B receptor 11p15.4 CDGS1A Carbohydrate-deficient glycoprotein syndrome type 1a 16p13 CD36L1 CD36 antigen (collagen type I receptor, thrombospondin receptor)-like 1 12q24.1-q24.3 CHOD Choroideremia with deafness Xq21.1-q21.2 COH1 Cohen syndrome 1 8q22-q23 CPE Carboxypeptidase E 4q32
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APPENDIX: Continued
Gene or locus Name Location D, F
DRD2 Dopamine receptor D2 11q23 ESD Esterase D/formylglutathione hydrolase 13q14.1-q14.2 ESR1† Estrogen receptor 1 6q25.1 FABP2 Fatty acid binding protein 2, intestinal 4q28-q31 FBS Fanconi–Bickel syndrome 3q26.1-q26.3 FGFR3 Fibroblast growth factor receptor 3 (achondroplasia, thanatophonic 4p16.3 dwarfism) FGF13 Fibroblast growth factor 13 Xq26 FPLD Familial partial lipodystrophy Dunnigan 1q21-q22
G–K
GCK Glucokinase (hexokinase 4, maturity onset diabetes of the young 2) 7p15.3-p15.1 GHRHR Growth hormone-releasing hormone-receptor 7p14 GLO1 Glyoxalase I 6p21.3-p21.1 GNAS1 Guanine nucleotide-binding protein (G protein), ␣-stimulating activity 20q13.2-q13.3 polypeptide 1 GNB3 Guanine nucleotide-binding protein (G protein),  polypeptide 3 12p13 GPC3 Glypican 3 Xq26.1 GPC4 Glypican 4 Xq26.1 GRL Glucocorticoid receptor 5q31-q32 GYPA Glycophorin A (includes MN blood group) 4q28.2-q31.1 GYS1 Glycogen synthase 1 (muscle) 19q13.3 HNF4A† Hepatocyte nuclear factor 4, alpha 20q12-q13.1 HNF6† Hepatocyte nuclear factor 6 8q24-q31 HSD3B1 Hydroxy-␦-5-steroid dehydrogenase, 3 -, and steroid ␦-isomerase 1 1p13.1 HTR2A 5-hydroxytryptamine (serotonin) receptor 2A 13q14-q21 HTR2C 5-hydroxytryptamine (serotonin) receptor 2C Xq24 IGF1 Insulin-like growth factor 1 (somatomedin C) 12q22-q23 IGF1R Insulin-like growth factor 1 receptor 15q25-q26 IGF2 Insulin-like growth factor 2 (somatomedin A) 11p15.5 IGHD Isolated growth hormone deficiency 7p15-p14 IGKC Immunoglobulin constant 2p12 INS Insulin 11p15.5 INSR Insulin receptor 19p13.3-p13.2 IRS Insulin resistance syndromes 19p13.3 IRS1 Insulin receptor substrate 1 2q36 ISL1 ISL1 transcription factor, LIM/homeodomain (islet-1) 5q22.3 KEL Kell blood group 7q33
L
LDLR Low-density lipoprotein receptor (familial hypercholesterolemia) 19p13.3 LEPR Leptin receptor 1p31 LEP Leptin (murine obesity homolog) 7q31.3
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APPENDIX: Continued
Gene or locus Name Location LIPC† Lipase, hepatic 15q21-q23 LIPE Lipase, hormone sensitive 19q13.1-q13.2 LMNA Lamin A/C 1q21.2-q21.3 LPL Lipoprotein lipase 8p22
M–O MC3R Melanocortin 3 receptor 20q13.2-q13.3 MC4R Melanocortin 4 receptor 18q22 MC5R Melanocortin 5 receptor 18p11.2 MEHMO Mental retardation, epileptic seizures, hypogonadism and genitalism, Xq22.13-p21.1 microcephaly, and obesity syndrome MKKS McKusick–Kaufman syndrome 20p12 MRXS7 Mental retardation, X-linked, syndromic 7 Xp11.3-Xq22.1 MYO9A Myosin IXA 15q22-q23 NDN Necdin (mouse) homolog 15q11.2-q12 NPY Neuropeptide Y 7p15.1 NPY5R Neuropeptide Y receptor Y5 4q31-q32 ORM1 Orosomucoid 1 9q31-q32 P–S P1 P blood group (P one antigen) 22q11.2-qter PCSK1 Proprotein convertase subtilisin/kexin type 1 5q15-q21 PGD Phosphogluconate dehydrogenase 1p36.2-p36.13 PMM2 Phosphomannomutase 2 16p13.3-p13.2 POMC Proopiomelanocortin 2p23.3 PON2 Paraoxonase 2 7q21.3 PPARG Peroxisome proliferative activated receptor, gamma 3p25 PPCD Posterior polymorphous corneal dystrophy 20q11 PROP1 Prophet of Pit-1, paired-like homeodomain transcription factor 5q PWS Prader–Willi syndrome 15q11-q13 SGBS1 Simpson–Golabi–Behmel syndrome 1 Xq26 SGBS2 Simpson–Golabi–Behmel syndrome 2 Xp22 SIM1 Single-minded (Drosophila) homolog 1 6q16.3-q21 SLC2A2 Solute carrier family 2 (facilitated glucose transporter), member 2 3q26.1-q26.2 SNRPN Small nuclear ribonucleoprotein polypeptide N 15q12 SUR1 Sulfonylurea receptor 1 11p15.1 T–W TBX3 T-box3 (ulnar mammary syndrome) 12q24.1 TCF1† Transcription factor 1, hepatic 12q24.2 TCF8 Transcription factor 8 (represses interleukin-2 expression) 10p11.2 THRB Thyroid hormone receptor- 3p24.3 THRS Thyroid hormone resistance syndrome 3p24.3 TNFA Tumor necrosis factor, alpha 6p21.3 TNFRSF1B Tumor necrosis factor receptor superfamily member 1B 1p36.3-p36.2 TUB Tubby (mouse) homolog 11p15.5 UCP1 Uncoupling protein 1 (mitochondrial, proton carrier) 4q28-q31 UCP2 Uncoupling protein 2 (mitochondrial, proton carrier) 11q13
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APPENDIX: Continued
Gene or locus Name Location UCP3 Uncoupling protein 3 (mitochondrial, proton carrier) 11q13 UMS Ulnar-Mammary syndrome Schinzel syndrome 12q23-q24.1 VDR† Vitamin D receptor 12q12-q14 WTS Wilson–Turner X-linked mental retardation syndrome Xp21.2-q22
* The gene symbols, names, and cytogenetic locations are from the Locus Link website (http://www.ncbi.nlm.nih.gov/LocusLink) available from the National Center for Biotechnology Information, which provides the official nomenclature of genetic loci. For the abbreviations of the Mendelian disorders, see Table 3. For the Mendelian disorders, the localization is from the Online Mendelian Inheritance in Man database. †Genes not found in the map and yielding negative results.
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