Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population

<div><p>Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (<em>MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO</em>); 2) localized novel genes in plausible biological pathways (<em>PCSK2, ARHGAP11A, CHRNA3</em>); and 3) revealed novel genes with unknown function in obesity pathogenesis (<em>MATK</em>, <em>COL4A1</em>). Salient findings include a nonsynonymous SNP (rs1056513) in <em>INADL</em> (<em>p</em> = 1.2E-07) for weight; an intronic variant in <em>MTNR1B</em> associated with fasting glucose (<em>p</em> = 3.7E-08); variants in the <em>APOA5-ZNF259</em> region associated with triglycerides (<em>p</em> = 2.5-4.8E-08); an intronic variant in <em>PCSK2</em> associated with total antioxidants (<em>p</em> = 7.6E-08); a block of 23 SNPs in <em>XPA/FOXE1</em> (<em>TTF-2</em>) associated with serum TSH (<em>p</em> = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (<em>p</em> = 1.3E-21), an intronic SNP (<em>p</em> = 3.6E-13) in <em>DARC</em> identified for MCP-1; an intronic variant in <em>ARHGAP11A</em> associated with sleep duration (<em>p</em> = 5.0E-08); and, after adjusting for body weight, variants in <em>MATK</em> for total energy expenditure (<em>p</em> = 2.7E-08) and in <em>CHRNA3</em> for sleeping energy expenditure (<em>p</em> = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.</p> </div

Joint Association of Nicotinic Acetylcholine Receptor Variants with Abdominal Obesity in American Indians: The Strong Heart Family Study

<div><p>Cigarette smoke is a strong risk factor for obesity and cardiovascular disease. The effect of genetic variants involved in nicotine metabolism on obesity or body composition has not been well studied. Though many genetic variants have previously been associated with adiposity or body fat distribution, a single variant usually confers a minimal individual risk. The goal of this study is to evaluate the joint association of multiple variants involved in cigarette smoke or nicotine dependence with obesity-related phenotypes in American Indians. To achieve this goal, we genotyped 61 tagSNPs in seven genes encoding nicotine acetylcholine receptors (nAChRs) in 3,665 American Indians participating in the Strong Heart Family Study. Single SNP association with obesity-related traits was tested using family-based association, adjusting for traditional risk factors including smoking. Joint association of all SNPs in the seven nAChRs genes were examined by gene-family analysis based on weighted truncated product method (TPM). Multiple testing was controlled by false discovery rate (FDR). Results demonstrate that multiple SNPs showed weak individual association with one or more measures of obesity, but none survived correction for multiple testing. However, gene-family analysis revealed significant associations with waist circumference (p = 0.0001) and waist-to-hip ratio (p = 0.0001), but not body mass index (p = 0.20) and percent body fat (p = 0.29), indicating that genetic variants are jointly associated with abdominal, but not general, obesity among American Indians. The observed combined genetic effect is independent of cigarette smoking <i>per se</i>. In conclusion, multiple variants in the nAChR gene family are jointly associated with abdominal obesity in American Indians, independent of general obesity and cigarette smoking <i>per se</i>.</p></div

Measured genotype analysis for endometabolic traits.

<p>Abbreviations: SNP, single nucleotide polymorphism; chr, chromosome; MGA, measured genotype analysis; nonsyn, nonsynonomous.</p><p>IGF-1, insulin-like growth factor-1; TSH, thyroid stimulating hormone; UTR, untranslated region; IGFBP3, binding protein 3.</p>*<p>Significant according to the widely used significance threshold p value of <5×10⁻⁸.</p>**<p>Significant according to the our population-specific significance threshold p value of <1.01×10⁻⁷.</p

Measured genotype analysis for diet, energy expenditure, substrate utilization and physical activity.

<p>Abbreviations: SNP, single nucleotide polymorphism; chr, chromosome; MGA, measured genotype analysis;</p><p>EER, estimated energy expenditure; UTR, untranslated region; RQ, respiratory quotient.</p>*<p>Significant according to the widely used significance threshold p value of <5×10^-8.</p>**<p>Significant according to the our population-specific significance threshold p value of <1.01×10⁻⁷.</p

Measured genotype analysis for anthropometric and body composition traits.

<p>Abbreviations: SNP, single nucleotide polymorphism; chr, chromosome; MGA, measured genotype analysis; nonsyn, nonsynonomous; BMI, body mass index; UTR, untranslated region.</p>*<p>Significant according to the widely used significance threshold p-value of <5×10⁻⁸.</p

Measured genotype analysis for inflammation markers.

<p>Abbreviations: SNP, single nucleotide polymorphism; chr, chromosome; MGA, measured genotype analysis; nonsyn, nonsynonomous;</p><p>MCP-1, monocyte chemotactic protein-1; UTR, untranslated region; IL-6, interluekin-6.</p>*<p>Significant according to the widely used significance threshold p value of <5×10⁻⁸.</p>**<p>Significant according to the our population-specific significance threshold p value of <1.01×10⁻⁷.</p

Gene-based and gene-family association of nAChRs variants with obesity (n = 3,640).

<p>P-values in bold indicates significant association after adjusting for multiple testing by FDR.</p

Characteristics of study participants according to smoking status (n = 3,640).

<p>^*P values were obtained by GEE, adjusting for age and sex when appropriate; ^‡ Former plus current smokers.</p

Fraction of GWAS-informative SNP pairs at different distance classes in domestic cat breeds.

<p>Colored lines represent selected populations that depict upper, middle, and lower examples whereas the gray lines represent the remaining populations (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0053537#pone.0053537.s012" target="_blank">Table S6</a>).</p

Population based SNP analysis of the domestic cat.

<p>Number of monomorphic SNPs (left) and SNPs with a minor allele frequency 0< MAF <0.05 (right). Legend corresponds to the ten chromosomal regions.</p