Genetic Diversity Of European Americans And Disease Gene Mapping

[Guest guest]

Genetic Diversity Of European Americans And Disease Gene Mapping

http://www.sciencedaily.com/releases/2008/01/080118093725.htm

Labels such as " European American " , " white " , or " Caucasian " are

often viewed as representing a homogeneous category in gene mapping

studies and census reports, but each of these labels actually groups

together multiple populations, which have diverse origins due to the

complex history of European immigration to the United States. In a

recent study an international team of researchers provide the first

genetic dissection of the population structure of European

Americans, focusing on identifying the contributions from different

genetic ancestries that are important for disease gene mapping.

This is a timely issue as the last year has seen a dramatic upswing

in genetic association studies and the discovery of almost a hundred

new risk factors for common genetic diseases such as cancer and

diabetes. If the subtle population substructure that exists within

European American populations is not understood and accounted for,

genetic association studies can produce incorrect findings if

disease cases are compared to healthy controls that on average have

different ancestry.

By systematically examining data from four actual disease

association studies in European Americans, this study describes and

characterizes the majority of population substructure in European

Americans that could lead to spurious associations. " Although our

work is far from a complete description of European American

population history, for the purpose of disease gene mapping studies

it is adequate to measure how closely each person's genetic ancestry

resembles three populations that can be roughly described as

northwest European, southeast European, or Ashkenazi Jewish, " says

Dr. Reich, one of the senior authors on the study, an

Associate Professor of Genetics at Harvard Medical School and an

Associate Member at the Broad Institute of Harvard and MIT. " With

this approach, we can avoid most false-positive associations due to

population substructure in European American disease gene mapping

studies. Our previous work has addressed related challenges in

studies of African Americans and Latino Americans. "

Based on their discovery that ancestry from only three populations

accounts for most of the potentially problematic substructure in

European American disease association studies, the researchers

scoured through published data sets to identify places in the genome

where common DNA sequence variants differ substantially in frequency

among these three ancestral populations and are therefore

potentially informative for estimating genetic ancestry.

The investigators then confirmed the utility of these genetic

variants by testing them in DNA samples that their coauthors

collected from the United Kingdom, Sweden, Poland, Spain, Italy,

Greece and U.S. Ashkenazi Jews. " We identified 300 common genetic

variants that have unusually different frequencies in the three

ancestral populations: they are about 10 times more informative for

predicting the ancestry of European Americans than random genetic

variants " , says lead author Dr. Alkes Price, a post-doctoral

researcher at the Harvard Medical School Department of Genetics and

the Broad Institute of Harvard and MIT. " We can thus correct for

population substructure in European American disease association

studies using just these 300 markers. "

This panel of 300 markers should be valuable in targeted associated

studies that follow up previously implicated candidate genes: by

comparing the ancestry of disease cases to healthy controls using

data from the panel of 300 markers, researchers can determine

whether observed associations are genuine, and not false-positives

due to population structure. The panel can also be used to match the

ancestry of cases and controls prior to more comprehensive studies.

While the technology should provide a new tool in disease gene

mapping studies, the researchers caution that the ability to roughly

categorize individuals into populations with a small number of

genetic markers is not useful in a clinical setting, nor does it

completely eliminate the utility of self-described

ethnicity. " Although these 300 markers give a reasonable estimate of

the major components of genetic ancestry in European Americans, self-

described ethnicity can still reflect environmental, social and

cultural factors that may not be captured by estimating genetic

ancestry, " says Dr. Hirschhorn, one of the senior authors of

the study, an Associate Professor of Genetics at Children's Hospital

Boston and Harvard Medical School, and a Senior Associate Member at

the Broad Institute of Harvard and MIT, " Because the genetic

differences between these populations are very small, the study is

most important for helping in gene discovery efforts, which will

lead to better understanding of human biology in health and disease,

and hopefully improved care for all patients over the long term. "

Published simultaneously in PLoS Genetics is an independent study

led by Seldin, in which Chao Tian and colleagues also

present panels of markers that can be used to correct for population

structure in European American disease association studies. A

commentary jointly authored by Seldin and Alkes Price on the

practical application of the panels developed by the two groups

accompanies these articles.

Title and full author list: " Discerning the Ancestry of European

Americans in Genetic Association Studies " PLoS Genetics.

Alkes L. Price*, Johannah , Nick , Cristian Capelli,

Vincenzo L. Pascali, Francesca Scarnicci, Andres Ruiz-Linares, Leif

Groop, A. Saetta, Penelope Korkolopoulou, Uri Seligsohn,

Alicja Waliszewska, Schirmer, Ardlie, is

Ramos, Nemesh, Lori Arbeitman, B. Goldstein,

Reich*, N. Hirschhorn*

* These three authors contributed equally