A novel genetic method """"""""Mapping by Admixture Linkage Disequilibrium"""""""" (MALD) has been proposed and implemented which provides a population- and patient cohort-based approach for disease gene identification. The method uses genetic markers with significant allele frequency differences between racial groups and a population with a recent history of admixture to identify novel disease genes involved in patient cohorts. This methodology is particularly appropriate for diseases where collecting large families for linkage analysis is difficult or where disease onset involves exposure to a common environmental or infectious agent. We have been collecting African American patients with breast and prostate cancer. The prostate cancer project is currently ongoing and we plan on beginning analysis of the other diseases like end-stage renal disease and focal segmental glomerulosclerosis as sufficient numbers of patients and controls are collected. We have screened 157 microsatellites from 352 African American and Hispanic prostate cancer patients and controls using markers from the MALD map which is in development (see Project Z01 BC 10270-05 LGD). The regions on chromosomes 1q24-25 and Xq27-28 identified by others in genetic linkage analyses are being carefully scrutinized in MALD analysis of prostate cancer. The remaining markers necessary to scan the genome at a 5- centiMorgan resolution are being chosen on the basis of maximal differences between African Americans and Hispanics vs. Caucasians, and our ability to efficiently perform multiplex analysis on an automated sequencer. A pause in this project has been taken as the markers that are available has increased markedly and the genotyping technologies are being optimized for higher throughput and minimal use of DNAs. The results of this project are being collected and analyzed on an ongoing basis. Positive signals for MALD linkage will be followed up by screening additional markers from the region for confirmation of the signal. Traditional disease gene identification methods which the laboratory has applied before will then be used to identify the genes involved in the etiology of prostate cancer.
| Chretien, J-P; Coresh, J; Berthier-Schaad, Y et al. (2006) Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans. J Med Genet 43:917-23 |
| Smith, Michael W; O'Brien, Stephen J (2005) Mapping by admixture linkage disequilibrium: advances, limitations and guidelines. Nat Rev Genet 6:623-32 |
| Smith, Michael W; Patterson, Nick; Lautenberger, James A et al. (2004) A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet 74:1001-13 |
