Body Mass Index Quantitative Trait Locus 1
Description
Body mass index (BMI), which reflects the amount of fat, lean mass, and body build, is a heterogeneous trait influenced by both genetic and environmental factors. Several studies have estimated the heritability of body mass index to be 40 to 55% (Bouchard et al., 1998; Rice et al., 1999).
For discussion of genetic heterogeneity of BMI quantitative trait loci and their known or possible associations with variation in specific genes, see MAPPING and MOLECULAR GENETICS sections.
Clinical FeaturesBMI is an informative and useful indicator of total fat mass, and a high BMI has been validated as an independent risk factor for coronary heart disease (Van Itallie and Abraham, 1985).
InheritanceAssociation With Asthma
In a study of 1,001 monozygotic and 383 dizygotic same-sex twin pairs, Hallstrand et al. (2005) analyzed self-reports of a physician diagnosis of asthma (see 600807) and BMI calculated using self-reported height and weight, and found a strong association between asthma and BMI (p less than 0.001). Substantial heritability was detected for asthma (53%) and obesity (77%), indicating additive genetic influences on each disorder. The best-fitting model of shared components of variance indicated that 8% of the genetic component of obesity is shared with asthma.
MappingBMIQ1 on Chromosome 7q31
Hsueh et al. (2001) performed a genomewide scan of obesity-related traits in 672 Amish individuals. For the trait BMI-adjusted leptin (164160) levels, they observed a lod score of 1.77 (P = 0.0022) on chromosome 7q (164 cM).
To identify regions that are likely to harbor quantitative trait loci (QTLs) for body mass index, Feitosa et al. (2002) conducted an autosomal genome scan for BMI through use of a variance components-based linkage analysis in families participating in the National Heart, Lung, and Blood Institute Family Heart Study. They found strong evidence for linkage on 7q32.3 in each of 2 samples and in the samples combined (maximum multipoint lod scores of 4.7 at marker GATA43C11 and 3.2 at marker D7S1804). The location of maximal linkage was near the reported location of the leptin gene (LEP; 164160) at 7q31.3.
Platte et al. (2003) performed a linkage association study of BMI in the Old Order Amish of southeastern Pennsylvania and concluded that a region of 7q distal to the leptin locus was responsible, at least in part, for variation in this measure of obesity.
BMIQ2 on Chromosome 13q14
See BMIQ2 (606643), which maps to chromosome 13q14.
BMIQ3 on Chromosome 6q23-q25
See BMIQ3 (607446), which maps to chromosome 6q23-q25.
BMIQ4 on Chromosome 11q24
See BMIQ4 (607447), which maps to chromosome 11q24. This locus is associated with variation in the UCP2 gene (601693).
BMIQ5 on Chromosome 16p13
See BMIQ5 (608558), which maps to chromosome 16p13.
BMIQ6 on Chromosome 20pter-p11.2
See BMIQ6 (608559), which maps to chromosome 20pter-p11.2.
BMIQ7 on Chromosome 4p15-p14
See BMIQ7 (608410), which maps to chromosome 4p15-p14.
BMIQ8 on Chromosome 10p
See BMIQ8 (603188), which maps to chromosome 10p.
BMIQ9 on Chromosome 20q
See BMIQ9 (602025), which maps to chromosome 20q. This locus is associated with variation in the MC3R gene (155540).
BMIQ10 on Chromosome 10q
See BMIQ10 (607514), which maps to chromosome 10q. This locus is associated with variation in the FFAR4 gene (609044).
BMIQ11 on Chromosome Xq24
See BMIQ11 (300306), which maps to chromosome Xq24.
BMIQ12 on Chromosome 5q15-q21
See BMIQ12 (612362), which maps to chromosome 5q15-q21. This locus is associated with variation in the PCSK1 gene (162150).
BMIQ13 on Chromosome 2q14.1
See BMIQ13 (612459), which maps to chromosome 2q14.1.
BMIQ14 on Chromosome 16q12.2
See BMIQ14 (612460), which maps to chromosome 16q12.2. This locus is associated with variation in the FTO gene (610966).
BMIQ15 on Chromosome 17q23.2-q25.1
See BMIQ15 (612967), which maps to chromosome 17q23.2-q25.1. This locus is associated with variation in the PRKCA gene (176960).
BMIQ16 on Chromosome 16p11.2
See BMIQ16 (see 613444), which maps to chromosome 16p11.2. This locus is associated with variation in the SH2B1 gene (608937), which is involved in a 220-kb chromosome 16p11.2 deletion syndrome (613444).
BMIQ17 on Chromosome 9p13.3
See BMIQ17 (614411), which is associated with variation in the AQP7 gene (602974) on chromosome 9p13.3.
BMIQ18 on Chromosome 6q14.2
See BMIQ18 (615457), which is associated with variation in the MRAP2 gene (615410) on chromosome 6q14.2.
BMIQ19 on Chromosome 2p23
See BMIQ19 (617885), which is associated with variation in the ADCY3 gene (600291) on chromosome 2p23.
BMIQ20 on Chromosome 18q21
See BMIQ20 (618406), which is associated with mutation in the MC4R gene (155541) on chromosome 18q21. BMIQ20 is a monogenic disorder characterized by severe obesity with hyperphagia or by resistance to obesity.
Genomewide Association Studies
Atwood et al. (2002) performed a genomewide linkage analysis of 6 separate measurements of body mass index taken over 28 years, from 1971 to 1998, in the Framingham Heart Study. There was substantial evidence for linkage on chromosome 11q24 in the area of markers D11S1998, D11S4464, and D11S912. (The location of these markers was incorrectly cited as 11q14 in the article.) The 6 measurements of BMI in that region showed maximum lod scores of 0.61, 3.27, 1.30, 0.68, 1.30, and 2.29. There was also evidence for linkage to 6q23-q25 (BMIQ3; 607446). Both of these regions had been implicated in previous studies (Feitosa et al., 2002; Hanson et al., 1998).
Yanagiya et al. (2007) analyzed 62,663 gene-based SNPs in 3 sequential case-control obesity studies and found a replicated association between obesity, defined as a BMI greater than or equal to 30 kg per meter squared, and a SNP (rs2293855) in the MTMR9 gene on chromosome 8p23-p22 (overall p value = 0.0000005).
Meyre et al. (2009) analyzed genomewide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls, with further evaluation of the 38 markers showing the strongest association in 14,186 European individuals. They identified novel associations with rs1805081 in the NPC1 gene (607623) on chromosome 18q11 (p = 2.9 x 10(-7)) and with rs1424233 near the MAF gene (177075) on chromosome 16q22-q23 (p = 3.8 x 10(-13)).
Walley et al. (2009) reviewed the genetic contribution to nonsyndromic human obesity, stating that despite the clear genetic component underlying obesity, genomewide association studies will not suffice to elucidate the genetic architecture of common obesity; they suggested that alternative study designs and additional obesity-related phenotype data will be required.
Speliotes et al. (2010) examined associations between body mass index and approximately 2.8 million SNPs in up to 123,865 individuals with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. Speliotes et al. (2010) confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P less than 5 x 10(-8)), one of which includes a copy number variant near GPRC5B (605948) on chromosome 16p12. Some loci, at MC4R (155541), POMC (176830), SH2B1, and BDNF (113505), mapped near key hypothalamic regulators of energy balance, and one of these loci was near GIPR (137241), an incretin (see 138030) receptor, on chromosome 19q13.
Kilpelainen et al. (2011) noted that while GWAS had identified 32 loci influencing body mass index to that time, this measure does not distinguish lean from fat mass. To identify adiposity loci, Kilpelainen et al. (2011) performed a metaanalysis of associations between 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (p less than 10(-6)) independent loci in 39,576 individuals. They confirmed the established adiposity locus in FTO (see BMIQ14, 612460) and identified 2 new loci associated with body fat percentage, one near IRS1 (147545) (rs2943650, effect allele T, combined p = 3.8 x 10(-11)) and one near SPRY2 (602466) (rs534870, effect allele A, combined p = 6.5 x 10(-8)). Kilpelainen et al. (2011) noted that the body fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes, and coronary artery disease, and decreased adiponectin levels.
Shungin et al. (2015) conducted genomewide association metaanalyses of traits related to waist and hip circumferences in up to 224,459 individuals and identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for BMI, as well as an additional 19 loci newly associated with related waist and hip circumference measures (p less than 5 x 10(-8)). In total, 20 of the 49 BMI-adjusted waist-to-hip ratio-associated loci showed significant sexual dimorphism; 19 of these displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution.
Locke et al. (2015) conducted a genomewide association study and custom genotype array metaanalysis of BMI in up to 339,224 individuals. Their analysis identified 97 BMI-associated loci (p less than 5 x 10(-8)). Five loci demonstrated clear evidence of several independent association signals, and many loci had significant effects on other metabolic phenotypes. The 97 loci accounted for approximately 2.7% of BMI variation, and genomewide estimates suggested that common variation accounts for greater than 20% of BMI variants. Pathway analyses provided strong support for a role of the central nervous system in obesity susceptibility and implicated new genes and pathways, including those related to synaptic function, glutamate signaling, insulin secretion/action, energy metabolism, lipid biology, and adipogenesis.
Molecular GeneticsFor a discussion of an association between variation in the ADIPOQ gene (605441) on chromosome 3q27 and BMI, see ADIPQTL1 (612556).
Modifier Loci
Several groups have presented evidence suggesting that a polymorphism in the PPARG2 gene (601487.0002) may modify BMI (Deeb et al., 1998; Valve et al., 1999; Masud and Ye, 2003).