Karen L. Mohlke | Department of Genetics

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Karen L. Mohlke, PhD
Assistant Professor

Research Interests
Key words: human genetics and genomics, diabetes, obesity, complex diseases

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 identify genes and nucleotide variants that alter disease susceptibility. Gene identification will likely result in 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 nonredundant 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.

Publications
Gaulton KJ, Mohlke KL, and Vision TJ (2007) A computational system to select candidate genes for complex human disorders. Bioinformatics. In press, Epub Jan 19, 2007

Willer CJ, Bonnycastle LL, Conneely KN, Duren WL, Jackson AU, Scott LJ, Narisu N, Chines PS, Petrie J, Erdos MR, Swift AJ, Enloe ST, Sprau AG, 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 SNPs previously associated with type 2 diabetes replicates association with twelve SNPs in nine genes. Diabetes 56:256-264

Bonnycastle LL, Willer CJ, Jackson AU, Burrill CP, Conneely KN, Watanabe RM, Chines PS, Narisu N, Scott LJ, Enloe ST, Swift AJ, Duren WL, Erdos MR, Riebow NL, Buchanan TA, Valle TT, Tuomilehto J, Bergman RN, Mohlke KL, Boehnke M, Collins FS (2006) Common variants in MODY genes contribute to risk of type 2 diabetes in Finns. Diabetes 55:2534-2540

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 T-cell transcription factor 7-like 2 (TCF7L2) variants with type 2 diabetes in a Finnish sample. Diabetes 55:2649-2653

Willer CJ, Scott LJ, Bonnycastle LL, Jackson AU, Chines PS, Pruim R, Bark CW, Tsai YY, Pugh EW, Doheny KF, Kinnunen L, Mohlke KL, Valle TT, Bergman RN, Tuomilehto J. Collins FS, Boehnke M (2006) Tag SNP Selection for Finnish Individuals based on the CEPH Utah HapMap Database. Genetic Epidemiology 30:180-190

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. Human Genetics 118:245-254

Mohlke KL and Boehnke M. The role of HNF4A variants in the risk of type 2 diabetes. (2005) Current Diabetes Reports 5:149-156

Mohlke KL, Skol AD, Scott LJ, Valle TT, Bergman RN, Tuomilehto J, Boehnke M, Collins FS. Evaluation of SLC2A10 (GLUT10) as a candidate gene for susceptibility to type 2 diabetes and related traits in Finns. (2005) Mol Gen Metab 85:323-327

Conneely KN*, Silander K*, Scott L, Mohlke KL, Lazaridis KN, Valle TT, Tuomilehto J, Bergman RN, Watanabe RM, Buchanan TA, Collins FS, Boehnke M (2004) Variation in the Resistin gene is associated with obesity and insulin-related phenotypes in Finnish subjects. Diabetologia, 47:1782-1788. * = these authors contributed equally to this work

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, Collins FS (2004) Genetic variation near the Hepatocyte Nuclear Factor-4 Alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141-1149.

Silander K, Valle TT, Scott LJ, Mohlke KL, Stringham HM, Wiles KR, Duren WL, Doheny K, Pugh E, Chines P, Narisu N, White PP, Watanabe RM, Fingerlin TE, Jackson AU, Li C, Colby K, Hollstein, P, Humphreys KM, Lambert J, Lazaridis KN, Lin G, Morales-Mena A, Patzkowski K, Pfahl C, Porter R, Rha D, Segal L, Suh Y, Tovar J, Unni A, Welch C, Douglas JA, Epstein M, Hauser ER, Hagopian W, Buchanan TA, Bergman RN, Tuomilehto J, Collins FS, Boehnke M (2004) A large set of Finnish affected sibling pair families with type 2 diabetes mellitus suggests susceptibility loci on chromosomes 6, 11, and 14. Diabetes 53, 821-829.

Mohlke KL,* Erdos MR,* Scott LJ,* Fingerlin TE, Jackson AU, Silander K, Hollstein P, Boehnke M, Collins FS (2002) High-throughput screening for evidence of association using mass spectrometry genotyping of single nucleotide polymorphisms. Proc Natl Acad Sci 99, 16928-16933

Fingerlin TE,* Erdos MR,* Watanabe RM, Wiles KR, Stringham HM, Mohlke KL, Silander K, Valle TT, Buchanan TA, Tuomilehto J, Bergman RN, Boehnke M and Collins FS (2002) Variation in three single nucleotide polymorphisms in the Calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort. Diabetes 51, 1644-1648

Mohlke KL,* Lange E,* Valle TT, Ghosh S, Magnuson VL, Silander K, Watanabe RM, Chines PS, Bergman RN, Tuomilehto J, Collins FS, and Boehnke M (2001) Linkage disequilibrium between microsatellite markers extends beyond 1 cM on chromosome 20 in Finns. Genome Research 11, 1221-1226

Douglas JA,* Erdos MR,* Watanabe RM, Braun A, Johnston CL, Oeth P, Mohlke KL, Valle T, Ehnholm C, Buchanan TA, Bergman RN, Collins FS, Boehnke M, Tuomilehto J (2001) The PPAR-gamma2 Pro12Ala variant: association with type 2 diabetes, trait differences, and interaction with the beta3-adrenergic receptor. Diabetes 50, 886-890

Ghosh S, Watanabe RM, Valle T, Hauser ER, Magnuson VL, Langefeld CD, Ally DS, Mohlke KL, Silander K, Kohtamaki K, Chines P, Porter R, Balow J, Musick A, Tannenbaum J, Te C, Segal L, Unni A, Karanjawala ZE, Rayman JB, Knapp JI, Whiten R, Birznieks G, Chang J, Eldridge W, Erdos MR, Kudelko K, Martin C, Morales-Mena A, Musick T, Pfahl C, Rha D, Shapiro S, Sharaf R, Shurtleff B, So A, Tovar J, Welch C, Witt A, Blaschak-Harvan J, Douglas JA, Duren WL, Epstein MP, Fingerlin TE, Kaleta H-S, Lange EM, Li C, McEachin RC, Stringham HM, Trager E, White PP, Eriksson J, Toivanen L, Vidgren G, Nylund SJ, Tuomilehto-Wolf E, Ross E, Demirchyan E, Hagopian WA, Buchanan TA, Tuomilehto J, Bergman RN, Collins FS, and Boehnke M (2000) The Finland-United States Investigation of Non-Insulin Dependent Diabetes Mellitus (FUSION) genetic study: I An autosomal genome scan for type 2 diabetes genes. Am J Hum Genet 67, 1174-1185

Watanabe RM, Ghosh S, Hauser ER, Langefeld C, Valle T, Magnuson VL, Mohlke KL, Silander K, Ally DS, Blaschak-Harvan J, Douglas JA, Duren WL, Epstein MP, Fingerlin TE, Kaleta H-S, Lange EM, Li C, McEachin RC, Stringham HM, Trager E, White PP, Balow J, Birznieks G, Chang J, Chines P, Eldridge W, Erdos MR, Karanjawala ZE, Knapp JI, Kudelko K, Martin C, Morales-Mena A, Musick A, Musick T, Pfahl C, Porter R, Rayman JB, Rha D, Segal L, Shapiro S, Sharaf R, Shurtleff B, So A, Tannenbaum J, Tovar J, Te C, Unni A, Welch C, Whiten R, Witt A, Kohtamaki K, Eriksson J, Toivanen L, Vidgren G, Nylund SJ, Tuomilehto-Wolf E, Ross E, Demirchyan E, Hagopian WA, Buchanan TA, Tuomilehto J, Bergman RN, Collins FS, and Boehnke M (2000) The Finland-United States Investigation of Non-Insulin Dependent Diabetes Mellitus (FUSION) genetic study: II An autosomal genome scan for quantitative trait loci. Am J Hum Genet 67, 1186-1200

Mohlke KL, Purkayastha AA, Westrick RJ, Smith PL, Petryniak B, Lowe JB, and Ginsburg D (1999) Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell 96, 111-20

Mohlke KL, Purkayastha AA, Westrick RJ, and Ginsburg D (1998) Comparative mapping of distal murine chromosome 11 and human 17q213 in a region containing a modifying locus for murine plasma von Willebrand factor level. Genomics 54, 19-30

Mohlke KL, Nichols WC, Westrick RJ, Novak EK, Cooney KA, Swank RT, and Ginsburg D (1996) A novel modifier gene for plasma von Willebrand factor level maps to distal mouse chromosome 11. Proc Natl Acad Sci 93, 15352-15357

Trainees
Kyle Gaulton, PhD Candidate, Curriculum in Genetics
Amanda Nave, PhD Candidate, Curriculum in Genetics

Contact Information
4109 Neuroscience Research Building, CB#7264
Chapel Hill, NC 27599-7264
919.966.2913
Email: mohlke<at>med.unc.edu

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