Genome-wide Association Studies Must Account For Ancestry

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Genome-wide Association Studies Must Account For Ancestry

http://www.medicalnewstoday.com/articles/134149.php

Ask someone where their ancestors were from and odds are that they

know. Or maybe not. A new study published in Human Molecular Genetics

suggests that scientists using the latest tools to scan the human

genome must pay attention to ancestry when analyzing and interpreting

their results.

Chao Tian and F. Seldin, MD, PhD, of University of California

, and K. Gregersen, MD, of The Feinstein Institute for

Medical Research, have identified allele frequency differences among

ethnic groups and subgroups that can result in statistical errors in

genetic studies and alter the outcome of the study.

Dr. Gregersen, head of the Feinstein's S. Boas Center for

Genomics and Human Genetics, said that about half of the Caucasian

people in the US who were asked where in Europe their ancestors came

from did not have a clue. Dr. Gregersen collaborated with Dr. Seldin

to identify a few thousand genetic markers that are powerful enough

to point to the region where an individual's ancestors once resided,

a tool that is much more reliable than asking a person about his or

her ancestry.

And this finding has more than just genealogical significance. In the

Human Molecular Genetics paper, they showed that it is critical to

account for ancestry in genome-wide association studies or the

results may not be accurate. " We believe the ancestral differences

should also be examined in the context of any clinical

epidemiological study, " the scientists concluded.

" Until now, scientists have depended on a person's knowledge of their

ancestral roots when they study human populations to look for risk

genes, " said Dr. Gregersen. " Even among racial groups there can be

significant differences in the frequencies of certain genetic

alleles. "

For instance, Dr. Gregersen studies rheumatoid arthritis, and in 2004

his team discovered an important risk gene called PTPN22. In the US,

the disease associated variant of PTPN22 is present in about eight-to-

10 percent of the population. Since the vast majority of Caucasians

living in the US had ancestors who once lived in Europe, the few

thousand genetic markers identified by Dr. Seldin were used to track

those with European origins. They tested the DNA from hundreds of

people in Europe and found that there was an enormous difference in

the frequency of the risk variant for PTPN22, according to whether a

person's ancestors are from southern vs. northern Europe. In Southern

Italy, for instance, only about three percent of the population had

this specific PTPN22 allele. Moving north into Sweden, about 12-to-15

percent of the population carries this variant. This variant

increases the risk for rheumatoid arthritis and a number of other

autoimmune conditions.

With these same genetic markers in hand - so called " ancestry

informative makers, " or " AIMs. " the scientists went after their US

sample, asking whether these markers could be used to identify where

a person's ancestors were from - even if the subjects themselves did

not know this information. Indeed, the study showed that they could.

Last month, Dr. Gregersen presented findings from their work at the

American Society of Human Genetics meetings in Philadelphia. The team

showed that these markers distinguish ancestry more precisely than

any tool available today. The genetic information is so specific that

one could look at genes from an Asian individual living in New York

and tell whether their ancestors migrated from Cambodia, Japan, Korea

or any other country in Asia.

Related studies have also shown that five-to-10 percent of Caucasians

have evidence of mixture with populations of Asian or African

descent, and Dr. Seldin's genetic markers can identify these

differences.

Going back to the PTPN22 gene, this team of investigators found that

it is not a risk factor for rheumatoid arthritis in the Asian

population. That means that if Asians were mixed into a genetic study

on rheumatoid arthritis it could greatly skew the findings.

" When you put thousands of these markers together, you get a

probability of who comes from Sweden or Southern Italy, " said Dr.

Gregersen. " This information is important if anyone wants to use

population studies to identify risk genes. These new genetic markers

are a powerful tool. The practical consequence is that we no longer

have to fully rely on a person's self report. It will increase a

scientist's confidence that their finding is not a spurious

association. "

In addition to the study in Human Molecular Genetics, the

investigators published a similar study in PLoS Genetics earlier this

year.

Feinstein Institute for Medical Research

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