GENETIC EPIDEMIOLOGY AND VARIANT DISCOVERY
The Genetic Epidemiology and Variant Discovery team are focused on the use of next generation sequencing methods to generate data to map genetic variation and applying population-based approaches to identify disease risk variants. Large population based studies using genome wide-association study (GWAS) approaches have identified more than 30 germline risk loci for ovarian cancer, and we are now focused on understanding how these loci increase disease risk, and how they direct disease initiation and progression.
Understanding how Ovarian Cancer risk loci increase disease risk.
Using genetic epidemiology tools to integrate genetic information with clinical, demographic and environmental data will improve risk estimation will allow clinicians to improve monitoring and disease prevention. We apply statistical approaches to model how germline risk variants combine with environmental risk factors to contribute to heritable disease risk. We are also using novel statistical methods to investigate how non-coding variants in gene regulatory regions contribute to heritability.
Identifying how Ovarian Cancer risk loci affect disease biology.
Now that we have identified a number of ovarian cancer risk loci it is critical that we understand how these variants lead to ovarian cancer. Functional annotation of risk loci with genomic datasets in collaboration with Dr. Dennis Hazelett and Simon Coetzee is combined with the “Jasmine’s Team” to identify the functional role of credible causal variants that are identified by fine mapping.
Mapping novel variants for Ovarian Cancer.
It is a major mission of the team to transition from SNP-array based studies to next-generation sequencing (with a particular focus on whole genome sequencing) studies for variant discovery. This includes developing pipelines for sample handling and quality control, data generation and informatics for data QC and analysis. Our current projects include the discovery of rare variants by exome and targeted sequencing panels. Planned projects using WGS will pursue the role of germline risk variants in somatic tissue and interrogate the accrual of mutations surrounding germline risk loci.
Identifying Rare Germline Variants by Exome Sequencing in Ovarian Cancer.
Screening Ovarian Cancer cohorts for Ovarian Cancer risk variants.
Identifying drivers of chemoresistance in recurrent OvCa.
Paritioning heritability of OvCa risk loci by genomic function.
Developing pipelines for WGS variant calling.
Identifying shared genetic risk between Polycystic Ovary Syndrome (PCOS) and Ovarian Cancer.
Jones MR, Brower M, Xu N, Cui J, Mengesha E, Chen Y-D, Taylor KD, Azziz R, Goodarzi MO. Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity. PLoS Genetics. 2015 Aug 25;11(8). PMID:26305227
Brower MA, Jones MR, Rotter JI, Krauss RM, Legro RS, Azziz R, Goodarzi MO. Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of chinese individuals. J Clin Endocrinol Metab. 2015 Jan;100(1). PMID: 25303487
Huertas-Vazquez A, Nelson CP, Guo X, Reinier K, Uy-Evanado A, Teodorescu C, Ayala J, Jerger K, Chugh H; WTCCC+, Braund PS, Deloukas P, Hall AS, Balmforth AJ, Jones M, Taylor KD, Pulit SL, Newton-Cheh C, Gunson K, Jui J, Rotter JI, Albert CM, Samani NJ, Chugh SS; Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease. PLoS One. 2013 Apr 4;8(4):e59905. PMID: 23593153
Goodarzi MO, Guo X, Cui J, Jones MR, Haritunians T, Xiang AH, Chen YD, Taylor KD, Buchanan TA, Hsueh WA, Raffel LJ, Rotter JI. Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance. Diabetologia. 2013 Jun;56(6):1282-90.PMID: 23494448.
Jones MR, Chazenbalk G, Xu N, Chua AK, Eigler T, Mengesha E, Chen YH, Lee JM, Pall M, Li X, Chen YD, Taylor KD, Mathur R, Krauss RM, Rotter JI, Legro RS, Azziz R, Goodarzi MO. Steroidogenic Regulatory Factor FOS Is Underexpressed in Polycystic Ovary Syndrome (PCOS) Adipose Tissue and Genetically Associated with PCOS Susceptibility. J Clin Endocrinol Metab. 2012 Sep;97(9):E1750-7. PMID: 22723319
Guo X, Cui J, Jones MR, Haritunians T, Xiang AH, Chen YD, Taylor KD, Buchanan TA, Davis RC, Hsueh WA, Raffel LJ, Rotter JI, Goodarzi MO. Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis. Diabetologia. 2012 Aug;55(8):2183-92. PMID: 22584727.
Jones MR, Chua AK, Mengesha EA, Taylor KD, Chen YD, Li X, Krauss RM, Rotter JI; Reproductive Medicine Network, Legro RS, Azziz R, Goodarzi MO. Metabolic and cardiovascular genes in polycystic ovary syndrome: a candidate-wide association study (CWAS). Steroids. 2012 Mar 10;77(4):317-22. PMID: 22178785.
Kenny EE, Pe'er I, Karban A, Ozelius L, Mitchell AA, Ng SM, Erazo M, Ostrer H, Abraham C, Abreu MT, Atzmon G, Barzilai N, Brant SR, Bressman S, Burns ER, Chowers Y, Clark LN, Darvasi A, Doheny D, Duerr RH, Eliakim R, Giladi N, Gregersen PK, Hakonarson H, Jones MR, Marder K, McGovern DP, Mulle J, Orr-Urtreger A, Proctor DD, Pulver A, Rotter JI, Silverberg MS, Ullman T, Warren ST, Waterman M, Zhang W, Bergman A, Mayer L, Katz S, Desnick RJ, Cho JH, Peter I. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet. 2012 Mar;8(3):e1002559. PMID:22412388.
Goodarzi MO, Jones MR, Li X, Chua AK, Garcia OA, Chen YD, Krauss RM, Rotter JI, Ankener W, Legro RS, Azziz R, Strauss JF 3rd, Dunaif A, Urbanek M. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet. 2012 Feb;49(2):90-5. PMID: 22180642.
Haritunians T, Jones MR, McGovern DP, Shih DQ, Barrett RJ, Derkowski C, Dubinsky MC, Dutridge D, Fleshner PR, Ippoliti A, King L, Leshinsky-Silver E, Levine A, Melmed GY, Mengesha E, Vasilauskas EA, Ziaee S, Rotter JI, Targan SR, Taylor KD. Variants in ZNF365 isoform D are associated with Crohn's disease. Gut. 2011 Jan 21. PMID: 21257989.
Ewens KG*, Jones MR*, Ankener W, Stewart DR, Urbanek M, Dunaif A, Legro RS, Chua A, Azziz R, Spielman RS, Goodarzi MO*, Strauss JF 3rd*. Type 2 diabetes susceptibility single-nucleotide polymorphisms are not associated with polycystic ovary syndrome. Fertil Steril. 2011 Jun 30;95(8):2538-41 PMID: 21444075. *Equal contribution.
Ewens KG*, Jones MR*, Ankener W, Stewart DR, Urbanek M, Dunaif A, Legro RS, Chua AK, Azziz R, Spielman RS, Goodarzi MO*, Strauss JF*, FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome, PLoS One, 2011 Jan 20;6(1):e16390. PMID: 21283731. *Equal contribution.
Jones MR, Chua A, Chen YD, Li X, Krauss RM, Rotter JI, Legro RS, Azziz R, Goodarzi MO. Harnessing expression data to identify novel candidate genes in polycystic ovary syndrome. PLoS One. 2011;6(5):e20120. PMID: 21611153.
Song Y, Altarejos J, Goodarzi MO, Inoue H, Guo X, Berdeaux R, Kim J-H, Goode J, Igata M, Paz J, Hogan MF, Singh P, Goebel N, Miller N, Cui J, Jones MR, Chen YDI, Taylor KD, Hsueh WA, Rotter JI, Montminy M. The CREB Coactivator CRTC3 Links Catecholamine Signaling to Energy Balance. Nature. 2010 Dec 16;468(7326):933-9. PMID: 21164481.
McGovern DP, Jones MR, Taylor KD, Marciante K, Yan X, Dubinsky M, Ippoliti A, Vasiliauskas E, Berel D, Derkowski C, Dutridge D, Fleshner P, Shih DQ, Melmed G, Mengesha E, King L, Pressman S, Haritunians T, Guo X, Targan SR, Rotter JI; Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. International IBD Genetics Consortium. Hum Mol Genet. 2010 Sep 1;19(17):3468-76. PMID: 20570966.
Wilson SG, Jones MR, Mullin BH, Dick IM, Richards JB, Pastinen TM, Grundberg E, Ljunggren O, Surdulescu GL, Dudbridge F, Elliott KS, Cervino AC, Spector TD, Prince RL. Common sequence variation in FLNB regulates bone structure in women in the general population and FLNB mRNA expression in osteoblasts in vitro. J Bone Miner Res. 2009 Dec;24(12):1989-97. PMID: 19453265.
Jones MR, Mathur R, Cui J, Guo X, Azziz R, Goodarzi MO. Independent confirmation of association between metabolic phenotypes of polycystic ovary syndrome and variation in the type 6 17beta-hydroxysteroid dehydrogenase gene. J Clin Endocrinol Metab. 2009 Dec;94(12):5034-8. PMID: 19837928.
Goodarzi MO, Taylor KD, Jones MR, Fang B, Guo X, Xiang AH, Buchanan TA, Hodis HN, Raffel LJ, Rotter JI. Replication of calpain-10 genetic association with carotid intima-media thickness. Atherosclerosis. 2009 Aug;205(2):503-5. PMID: 19193380.
Jones MR, Wilson SG, Mullin BH, Mead R, Dudbridge F, Watts GF, Stuckey BG. Polymorphism in postinsulin receptor signaling pathway is not associated with polycystic ovary syndrome. Fertil Steril. 2008 Dec;90(6):2298-303. PMID: 18249389.
Jones MR, Wilson SG, Mullin BH, Mead R, Watts GF, Stuckey BG. Polymorphism of the follistatin gene in polycystic ovary syndrome. Mol Hum Reprod 2007 Apr;13(4):237-4. PMID: 17284512
Jones MR, Italiano L, Wilson SG, Mullin BH, Mead R, Dudbridge F, Watts GF, Stuckey BG. Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome. Fertil Steril. 2006 Nov;86(5):1438-46. PMID: 17070195