Dataset Information

The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.

ABSTRACT: Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted.The exons of FTO, MC4R, and TMEM18 in an initial subset of our cohort were sequenced, that is, 200 obese (BMI ? 95 th percentile) and 200 lean AA children (BMI ? 5 th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI?50th percentile) children of the same ethnicity.A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V, and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S, and I251L), and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R (Fisher's exact P = 0.0001).In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.

SUBMITTER: Deliard S

PROVIDER: S-EPMC3605748 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.

Deliard Sandra S Panossian Saarene S Mentch Frank D FD Kim Cecilia E CE Hou Cuiping C Frackelton Edward C EC Bradfield Jonathan P JP Glessner Joseph T JT Zhang Haitao H Wang Kai K Sleiman Patrick M A PM Chiavacci Rosetta M RM Berkowitz Robert I RI Hakonarson Hakon H Zhao Jianhua J Grant Struan F A SF

Obesity (Silver Spring, Md.) 20130101 1

<h4>Objective</h4>Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted.<h4>Design and methods</h4>The exons of FTO, MC4R, and TMEM18 in an initial su ...[more]

PMID: 23505181

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Project description:ImportanceNumerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction.ObjectiveTo determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk.Design, setting, and participantsCase-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry.ExposuresTwo APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype.Main outcomes and measuresThe primary outcome was AD case-control status, and secondary outcomes included age at AD onset.ResultsStage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (β, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (β, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (β, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H.Conclusions and relevanceIn this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Dataset Information

The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.

Publications

The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry.

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