Common traits with complex inheritance patterns have both genetic and environmental causes. Type 2 diabetes and obesity are examples of complex metabolic disorders with a strong genetic component. Genetic association studies provide a promising approach to identifying genes and nucleotide variants that alter disease susceptibility. Gene identification will likely result in a better understanding of disease etiology, and has the potential to help identify at-risk individuals, to suggest new drug targets and therapies, and to assist in preventing disease.

Type 2 diabetes
The Mohlke lab uses  genome-wide approaches to localize diabetes-susceptibility genes as part of the Finland United States Investigation of NIDDM Genetics (FUSION) study. This study includes more than 6000 Finnish individuals affected with type 2 diabetes or with normal glucose tolerance. To identify the underlying disease alleles, single nucleotide polymorphisms (SNPs) are tested for evidence of association with type 2 diabetes and related quantitative traits. SNPs being studied span the human genome, and special emphasis is given to SNPs located near a set of high-priority genes. Common non-redundant SNPs are identified from genome databases and rare SNPs are identified by resequencing.

Weight gain
To investigate the role of genetics in weight gain and other traits associated with cardiovascular risk, the lab is partnering with investigators from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). This study includes ~3700 individuals in the Philippines for whom 20 years of anthropometric, lifestyle, and environmental data exist. Traits include longitudinal weight gain and related obesity measures, as well as the early origins of adult chronic diseases. In addition to examining the primary effects of genes, the lab is exploring the interaction of genes with environmental risk factors in disease pathogenesis.

Pathogenic mechanisms
A long-term goal of the Mohlke lab is to understand the biological function of susceptibility alleles identified through genome-wide studies. Hypothesizing that many common disease variants will have a regulatory effect on gene function, the lab is evaluating allelic-expression differences in mice.

Ultimately, the lab will create mouse models to compare high- and low-risk alleles in a whole-animal setting. Mice harboring the risk allele or haplotype will be used to examine interactions with diet, other environmental factors, and additional genes that may be relevant to diabetes and obesity.

Selected publications:
Gaulton KJ, Mohlke KL, Vision TJ. (2007) A computational system to select candidate genes for complex human traits. Bioinformatics. Feb 21; [Epub ahead of print]

Willer CJ, Bonnycastle LL, Conneely KN, Duren WL, Jackson AU, Scott LJ, Narisu N, Chines PS, Skol A, Stringham HM, Petrie J, Erdos MR, Swift AJ, Enloe ST, Sprau AG, Smith E, Tong M, Doheny KF, Pugh EW, Watanabe RM, Buchanan TA, Valle TT, Bergman RN, Tuomilehto J, Mohlke KL, Collins FS, Boehnke M. (2007) Screening of 134 single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes. Diabetes. 56:256-64.

Scott LJ, Bonnycastle LL, Willer CJ, Sprau AG, Jackson AU, Narisu N, Duren WL, Chines PS, Stringham HM, Erdos MR, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Collins FS, Boehnke M. (2006) Association of transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes. 55:2649-53.

Mohlke KL, Jackson AU, Scott LJ, Peck EC, Suh YD, Chines PS, Watanabe RM, Buchanan TA, Conneely KN, Erdos MR, Narisu N, Enloe S, Valle TT, Tuomilehto J, Bergman RN, Boehnke M, Collins FS. (2005) Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns. Hum Genet 118:245-54.

Mohlke KL, Skol AD, Scott LJ, Valle TT, Bergman RN, Tuomilehto J, Boehnke M, Collins FS (2005) FUSION Study Group.Evaluation of SLC2A10 (GLUT10) as a candidate gene for type 2 diabetes and related traits in Finns. Mol Genet Metab 85:323-7.

Silander K,* Mohlke KL,* Scott LJ, Peck EC, Hollstein P, Skol AD, Jackson AJ, Deloukas P, Hunt S, Stavrides G, Chines PS, Erdos MR, Narisu N, Conneely KN, Li C, Fingerlin TE, Dhanjal SK, Valle TT, Bergman RN, Tuomilehto J, Watanabe RM, Boehnke M and Collins FS (2004) Genetic variation near the Hepatocyte Nuclear Factor-4 Alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141-1149.
 

 

 

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