DNAprint Genomics (DNAG)

[mingwan0]

Here's another admixture mapping study:

http://www.nationalmssociety.org/Research-Hafler3.asp

David A. Hafler, MD
Whitehead Institute for Biomedical Research Cambridge, MA
Region: Central New England Chapter
Award: Research Grant
Term/Amount: 4/1/04-3/31/07; $670,788

Funded by the NMSS Central New England chapter, in part by gifts from Barbara Palmer

“A whole genome admixture scan for the multiple sclerosis genes” Scanning for MS genes in genetic material from patients whose ancestry contain a mix of populations at high risk and at low risk for MS.

Although MS is not inherited directly, there appears to be a genetic predisposition to developing the disease. Evidence indicates that a single gene alone does not determine the risk of getting MS. Many separately inherited genes appear to contribute to MS susceptibility, making the search more complex. David A. Hafler, MD, is using a new and powerful technique called “admixture mapping” to identify MS genes.

As it relates to MS, admixture mapping involves studying the genetic basis of MS in populations with mixed racial ancestry. MS in African-Americans is clinically similar to that seen in European-Americans (Caucasians). However, African-Americans have only one-half the risk of developing MS when compared to those of European extraction. Continental Africans have an even lower rate of MS than African-Americans. These facts suggest that genetic susceptibility to MS in African-Americans may lie in the genetic material that might have been inherited from a European ancestor.

Dr. Hafler’s team is studying genetic material from 1000 African-Americans with MS, collected by Jorge Oksenberg, PhD, and Stephen Hauser, MD (University of California at San Francisco) with separate funding from National MS Society. They are identifying which parts are of European ancestry, and are looking for small overlapping regions that may contain MS genes.

This study should help to identify MS genes not only in African-Americans but will help to pinpoint MS susceptibility genes in the general population as well, and may provide targets for the development of new drugs for MS.

There's a coincidence because this lot are also working on admixture mapping and MS:

http://maths.dur.ac.uk/php/seminars.php3?series=MG&identifier=2302&parent_page=timetable

LMS Durham Symposium: Mathematical Genetics

Dr David Reich (Harvard Department of Genetics)
High density admixture mapping to find genes for complex disease and application to multiple sclerosis

Abstract:

(Joint work with N Patterson, N Hattangadi, MW Smith, SJ O’Brien, PD Jager, MJ Daly, D Altshuler, JR Oksenberg, SL Hauser and DA Hafler)

Admixture mapping is a powerful way, in principle, to carry out whole-genome scans for disease genes. The method in theory requires ~100 times fewer markers than whole-genome haplotype mapping, but should have similar statistical power to detect disease variants that differ strikingly in frequency across populations. The key idea of admixture mapping is that near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles from the group with greater disease susceptibility. Since gene flow occurred recently (in African and Hispanic Americans in the past 20 generations), recombination has not had much time to act and linkage disequilibrium should extend many centimorgans.

Admixture mapping has never previously been used to identify a gene associated with a disease. One reason is that there was no high density map with large frequency differences across populations. Here we report 3 results suggesting that admixture mapping should soon be a practical method for mapping genes for complex disease in African Americans.

• We have generated a map of 2,154 SNPs with average frequency difference of 57% between Africans and Europeans. These were chosen from ~450,000 SNPs with known Africans and European frequencies, and revalidated in a new set of 378 samples to confirm their appropriateness for admixture mapping.

• We have developed methods that allow analysis of data from such a high density map. Applying the approach to two data sets we have collected in the laboratory, we show that strong admixture linkage disequilibrium extends, on average, 17 cM in African Americans. Power calculations show that ~2,000 markers in ~2,000 patients can provide high power to detect disease loci.

• Finally, we have applied whole-genome admixture mapping for the first time to a complex human disease (multiple sclerosis). We will report preliminary results from 756 SNPs genotyped in 712 cases and controls, which allow us to scan for admixture association.

Some recent papers:

Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, Malasky MJ, Scafe C, Le E, De Jager PL, Mignault AA, Yi Z, De The G, Essex M, Sankale JL, Moore JH, Poku K, Phair JP, Goedert JJ, Vlahov D, Williams SM, Tishkoff SA, Winkler CA, De La Vega FM, Woodage T, Sninsky JJ, Hafler DA, Altshuler D, Gilbert DA, O'Brien SJ, Reich D. A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet. 2004 May;74(5):1001-13. Epub 2004 Apr 14.

Patterson N, Hattangadi N, Lane B, Lohmueller KE, Hafler DA, Oksenberg JR, Hauser SL, Smith MW, O'Brien SJ, Altshuler D, Daly MJ, Reich D. Methods for high-density admixture mapping of disease genes. Am J Hum Genet. 2004 May;74(5):979-1000. Epub 2004 Apr 14.