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Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level

Olivier Harismendy12, Vikas Bansal3, Gaurav Bhatia4, Masakazu Nakano12, Michael Scott5, Xiaoyun Wang12, Colette Dib6, Edouard Turlotte6, Jack C Sipe5, Sarah S Murray3, Jean Francois Deleuze6, Vineet Bafna47, Eric J Topol35 and Kelly A Frazer127*

Author affiliations

1 Moores UCSD Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

2 Department of Pediatrics and Rady's Childrens Hospital, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

3 Scripps Genomic Medicine, Scripps Translational Science Institute, 3344 North Torrey Pines Court Suite 300, La Jolla, CA 92037, USA

4 Department of Computer Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

5 Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA

6 Sanofi-Aventis Evry Genetics Center, 2 rue Gaston Cremieux, 91057 Evry, France

7 Institute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA

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Citation and License

Genome Biology 2010, 11:R118  doi:10.1186/gb-2010-11-11-r118

Published: 30 November 2010

Abstract

Background

Targeted re-sequencing of candidate genes in individuals at the extremes of a quantitative phenotype distribution is a method of choice to gain information on the contribution of rare variants to disease susceptibility. The endocannabinoid system mediates signaling in the brain and peripheral tissues involved in the regulation of energy balance, is highly active in obese patients, and represents a strong candidate pathway to examine for genetic association with body mass index (BMI).

Results

We sequenced two intervals (covering 188 kb) encoding the endocannabinoid metabolic enzymes fatty-acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) in 147 normal controls and 142 extremely obese cases. After applying quality filters, we called 1,393 high quality single nucleotide variants, 55% of which are rare, and 143 indels. Using single marker tests and collapsed marker tests, we identified four intervals associated with BMI: the FAAH promoter, the MGLL promoter, MGLL intron 2, and MGLL intron 3. Two of these intervals are composed of rare variants and the majority of the associated variants are located in promoter sequences or in predicted transcriptional enhancers, suggesting a regulatory role. The set of rare variants in the FAAH promoter associated with BMI is also associated with increased level of FAAH substrate anandamide, further implicating a functional role in obesity.

Conclusions

Our study, which is one of the first reports of a sequence-based association study using next-generation sequencing of candidate genes, provides insights into study design and analysis approaches and demonstrates the importance of examining regulatory elements rather than exclusively focusing on exon sequences.