Charles R. Farber
Assistant Professor of Medicine and Biochemistry & Molecular Genetics
Ph.D., University of California, Davis
Systems Genetics of Complex Disease

 

Osteoporosis is a common disease characterized by bone fragility. Many intrinsic characteristics of bone, including its size, shape and mineral density, contribute to fragility. Most of these traits are primarily controlled by genetics; therefore, dissecting the genetic basis of variation in bone holds promise for developing a much more comprehensive understanding of the mechanisms contributing to osteoporosis.

Historically, geneticists have dissected the genetics of complex bone traits in a strictly DNA-centric fashion (i.e. directly linking changes in DNA with changes in a phenotype). However, new technologies have paved the way to interrogate other components of a cell, tissue or organism at unprecedented resolution. These advances have enabled the quantification of molecular phenotypes such as DNA methylation (methylome), gene expression levels (transcriptome) and protein levels (proteome), on a genome-wide scale. Now geneticists have the ability to analyze the effects of genetic variation, not just on clinical endpoints, but also on many intermediate molecular phenotypes. These data can be used to generate cellular networks and then determine how DNA variation leads to disease by perturbing these networks.

This new field is referred to Systems and our lab uses this approach to understand how genetic variation influences bone and bone cell activities. The biological component that we utilize for systems genetics is most often the transcriptome. This is due to the widespread use of DNA microarrays, which allow one to measure the expression levels of nearly all genes in a genome. Currently our lab is using the systems genetics analysis of transcriptomic data in the mouse to identify genes, biological pathways and gene networks that affect bone development. We are also using systems genetics to develop a more comprehensive view of how specific transcriptional networks regulation the function of osteoblasts, the cells that form new bone.


Selected References

Hsu YH, Zillikens MC, Wilson SG, Farber CR, Demissie S, Soranzo N, Bianchi EN,Grundberg E, Liang L, Richards JB, Estrada K, Zhou Y, van Nas A, Moffatt MF,Zhai G, Hofman A, van Meurs JB, Pols HA, Price RI, Nilsson O, Pastinen T,Cupples LA, Lusis AJ, Schadt EE, Ferrari S, Uitterlinden AG, Rivadeneira F,Spector TD, Karasik D, Kiel DP. (2010) "An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits." PLoS Genet. Jun 6:e1000977. [PubMed]

Farber CR. (2010) "Identification of a gene module associated with BMD through the integration of network analysis and genome-wide association data." J Bone Miner Res. 25(11):2359-67. [PubMed]

Bennett BJ, Farber CR, Orozco L, Kang HM, Ghazalpour A, Siemers N, Neubauer M,Neuhaus I, Yordanova R, Guan B, Truong A, Yang WP, He A, Kayne P, Gargalovic P,Kirchgessner T, Pan C, Castellani LW, Kostem E, Furlotte N, Drake TA, Eskin E,Lusis AJ. (2010) "A high-resolution association mapping panel for the dissection of complex traits in mice." Genome Res. 20:281-90. Epub 2010 Jan 6. [PubMed]

Suwanwela J, Farber CR, Haung BL, Song B, Pan C, Lyons KM, Lusis AJ. (2010) "Systems genetics analysis of mouse chondrocyte differentiation." J Bone Miner Res. Oct [Epub ahead of print] [PubMed]

Farber CR, Lusis AJ. (2009) "Future of osteoporosis genetics: enhancing genome-wide association studies." J Bone Miner Res. 24(12):1937-42. [PubMed]

Yang X, Deignan JL, Qi H, Zhu J, Qian S, Zhong J, Torosyan G, Majid S, FalkardB, Kleinhanz RR, Karlsson J, Castellani LW, Mumick S, Wang K, Xie T, Coon M,Zhang C, Estrada-Smith D, Farber CR, Wang SS, van Nas A, Ghazalpour A, Zhang B,Macneil DJ, Lamb JR, Dipple KM, Reitman ML, Mehrabian M, Lum PY, Schadt EE,Lusis AJ, Drake TA. (2009) "Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks." Nat Genet. 41:415-23. Epub 2009 Mar 8. [PubMed]

Farber CR, van Nas A, Ghazalpour A, Aten JE, Doss S, Sos B, Schadt EE,Ingram-Drake L, Davis RC, Horvath S, Smith DJ, Drake TA, Lusis AJ. (2009) "An integrative genetics approach to identify candidate genes regulating BMD: combining linkage, gene expression, and association." J Bone Miner Res. 24:105-16. [PubMed]