The central focus of our research program is how dysregulation of lipid uptake and trafficking contributes to human diseases. Since the optimal strategy to identify functional sequence variations contributing to disease depends on the underlying genetic architecture of the trait, we have used three complementary approaches:
- Resequencing extremes: To identify alleles of large phenotypic effect, we resequenced candidate genes in individuals with extreme phenotypes in the general population (1). This strategy has revealed that severe loss-of-function alleles are more common than previously recognized, and provided the first direct evidence that rare variants play an important role in complex traits in the general population (1-3). The power of the “resequencing extremes” strategy is best illustrated by identification of loss-of-function alleles in PCSK9, which confer modest reductions in LDL-C and substantial protection against CHD (2,4).
- Resequencing populations: Our “resequencing extremes” strategy suggested that severe loss-of-function alleles may be sufficiently common to allow a reverse genetics approach to determine the roles of genes in human physiology. We hypothesized that the phenotypic consequences of sequence variations in genes can be defined by sequencing large cohorts of well-characterized individuals. This approach was used to determine the effects of loss-of-function mutations in angiopoeitin-like proteins (ANGPTL3-5) in humans (5,6).
- Genome-wide association studies (GWAS): To identify novel genes, we performed unbiased large-scale association studies in a large population with uniform, comprehensive phenotyping, the Dallas Heart Study. This approach yielded the first genetic locus that is directly associated with CHD independent of known risk factors (7), and the first gene associated with nonalcoholic fatty liver disease (8).
- Whole genome sequencing: The development of massively parallel DNA sequencing allows accurate resequencing of the whole-genome (or exome) of selected individuals. We are using this technology to identify disease-causing mutations in individuals with atypical disorders of lipid metabolism (see reference 9).
These genes provide molecular handles for mechanistic studies to define key pathways in lipid metabolism. A major focus of our research effort is to elucidate the role of PCSK9, PNPLA3, and the ANGPTL proteins in the trafficking and processing of lipids and lipoproteins.
- Cohen J.C., Kiss R.S., Pertsemlidis A., Marcel Y.L., McPherson R., Hobbs H.H. (2004) Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305: 869-872.
- Cohen J.C., Pertsemlidis A., Kotowski I.K., Graham R., Garcia C. K., Hobbs H.H. (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37: 161-165.
- Cohen J.C., Pertsemlidis A., Fahmi S., Esmail S., Vega G.L., Grundy S.M., Hobbs H.H. (2006) Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc. Natl. Acad. Sci. USA 103: 1810-1815.
- Cohen J.C., Boerwinkle E., Mosley T.H., Hobbs H.H. (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354: 1264-72.
- Romeo S., Pennacchio L.A., Fu Y., Boerwinkle E., Tybjaerg-Hansen A., Hobbs H.H., Cohen, JC (2007) Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39: 513-516.
- Romeo S., Yin W., Kozlitina J., Pennacchio L.A., Boerwinkle E., Hobbs H.H., Cohen J.C. (2009) Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119:70-79. PMCID:PMC2613476
- McPherson R., Pertsemlidis A., Kavaslar N., Stewart A., Roberts R., Cox D.R., Hinds D.A., Pennacchio L.A., Tybjaerg-Hansen A., Folsom A.R., Boerwinkle E., Hobbs H.H., Cohen J.C. (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316: 1488-91. PMCID: PMC271874
- Romeo S., Kozlitina J., Xing C., Pertsemlidis A., Cox D., Pennacchio L.A., Boerwinkle E., Cohen J.C., Hobbs, H.H. (2008). Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40: 1461-5. PMCID: PMC2597056
- Rios J., Stein E., Shendure J., Hobbs H. H., Cohen J.C. (2010) Identification by whole genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum. Mol. Genet., In Press. PMID: PMC Journal - In Process