A Genome Scan for Fasting Insulin and Fasting Glucose Identifies a Quantitative Trait Locus on Chromosome 17p: The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of CCNL1 contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of MAST3, whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of SLC5A11. Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of POMC, ADCY3 and DNAJC27. In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.

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Association Analysis Indicates That a Variant GATA-Binding Site in the PIK3CB Promoter Is a Cis-Acting Expression Quantitative Trait Locus for This Gene and Attenuates Insulin Resistance in Obese Children

Diabetes ◽

10.2337/db07-1273 ◽

2007 ◽

Vol 57 (2) ◽

pp. 494-502 ◽

Cited By ~ 18

Author(s):

C. Le Stunff ◽

A. Dechartres ◽

V. Mariot ◽

C. Lotton ◽

C. Trainor ◽

...

Keyword(s):

Insulin Resistance ◽

Quantitative Trait Locus ◽

Binding Site ◽

Association Analysis ◽

Quantitative Trait ◽

Expression Quantitative Trait Locus ◽

Obese Children ◽

Cis Acting ◽

Trait Locus

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Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17

Physiological Genomics ◽

10.1152/physiolgenomics.00275.2004 ◽

2005 ◽

Vol 21 (1) ◽

pp. 112-116 ◽

Cited By ~ 19

Author(s):

Myrian Grondin ◽

Vasiliki Eliopoulos ◽

Raphaelle Lambert ◽

Yishu Deng ◽

Anita Ariyarajah ◽

...

Keyword(s):

Blood Pressure ◽

Quantitative Trait Locus ◽

Quantitative Trait ◽

Congenic Strain ◽

Chromosome 17 ◽

Congenic Strains ◽

Genome Wide ◽

A Genome ◽

Trait Locus ◽

Negative Controls

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

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A quantitative trait locus influencing estrogen levels maps to a region homologous to human chromosome 20

Physiological Genomics ◽

10.1152/physiolgenomics.2001.5.2.75 ◽

2001 ◽

Vol 5 (2) ◽

pp. 75-80 ◽

Cited By ~ 11

Author(s):

LISA J. MARTIN ◽

JOHN BLANGERO ◽

JEFFREY ROGERS ◽

MICHAEL C. MAHANEY ◽

JAMES E. HIXSON ◽

...

Keyword(s):

Quantitative Trait Locus ◽

Human Chromosome ◽

Quantitative Trait ◽

Potential Candidate ◽

General Pedigree ◽

Genome Wide ◽

A Genome ◽

Component Approach ◽

Trait Locus ◽

Variance Component Approach

Estrogen, a steroid hormone, regulates reproduction and has been implicated in several diseases. We performed a genome-wide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in estrogen levels in baboons. A microsatellite polymorphism, D20S171, located on human chromosome 20q13.11, showed strong evidence of linkage with a LOD score of 3.06 ( P = 0.00009). This region contains several potential candidate genes including melanocortin 3 receptor ( MC3R), cytochrome P-450 subfamily XXIV ( CYP24), and breast carcinoma amplified sequence ( BCAS1). This is the first evidence of a quantitative trait locus with a significant effect on estrogen.

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Identification of Quantitative Trait Loci for Glucose Homeostasis: The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

Diabetes ◽

10.2337/diabetes.53.7.1866 ◽

2004 ◽

Vol 53 (7) ◽

pp. 1866-1875 ◽

Cited By ~ 45

Author(s):

S. S. Rich ◽

D. W. Bowden ◽

S. M. Haffner ◽

J. M. Norris ◽

M. F. Saad ◽

...

Keyword(s):

Insulin Resistance ◽

Quantitative Trait Loci ◽

Glucose Homeostasis ◽

Quantitative Trait ◽

Family Study ◽

Trait Loci ◽

Insulin Resistance Atherosclerosis Study

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A Quantitative Trait Locus on Chromosome 13q Affects Fasting Glucose Levels in Hispanic Children

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-1695 ◽

2007 ◽

Vol 92 (12) ◽

pp. 4893-4896 ◽

Cited By ~ 9

Author(s):

Guowen Cai ◽

Shelley A. Cole ◽

Nancy F. Butte ◽

V. Saroja Voruganti ◽

Anthony G. Comuzzie

Keyword(s):

Quantitative Trait Locus ◽

Quantitative Trait ◽

Fasting Glucose ◽

Serum Glucose ◽

Fasting Serum ◽

Hispanic Children ◽

Fasting Serum Glucose ◽

Glucose Levels ◽

Trait Locus ◽

Chromosome 13Q

Abstract Objective: The prevalence of childhood obesity has increased dramatically in the United States. Early presentation of type 2 diabetes has been observed in children and adolescents, especially in the Hispanic population. The genetic contribution of glucose homeostasis related to childhood obesity is poorly understood. The objective of this study was to localize quantitative trait loci influencing fasting serum glucose levels in Hispanic children participating in the Viva La Familia Study. Design: Subjects were 1030 children ascertained through an overweight child from 319 Hispanic families. Fasting serum glucose levels were measured enzymatically, and genetic linkage analyses were conducted using SOLAR software. Results: Fasting glucose was heritable, with a heritability of 0.62 ± 0.08 (P < 0.01). Genome-wide scan mapped fasting serum glucose to markers D13S158–D13S173 on chromosome 13q (LOD score of 4.6). A strong positional candidate gene is insulin receptor substrate 2, regulator of glucose homeostasis and a candidate gene for obesity. This region was reported previously to be linked to obesity- and diabetes-related phenotypes. Conclusions: A quantitative trait locus on chromosome 13q contributes to the variation in fasting serum glucose levels in Hispanic children at high risk for obesity.

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