Certain genetic variants linked to sex differences in Parkinson’s risk

Genetic factors appear to contribute to higher disease risk in men, study says

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers have identified regions of DNA that appear to influence both Parkinson’s disease risk and sex-specific factors, including age of menstruation and menopause.

Variants in these regions had different effects on gene activity in men and women, which scientists believe could underlie the higher prevalence of the neurodegenerative disease in men.

Findings overall “point to candidate genes for future studies that could possibly explain the higher incidence of Parkinson’s disease in males,” researchers wrote. “Potentially protective biological processes could be future targets for disease modifying drugs.”

The study, “Pleiotropy with sex-specific traits reveals genetic aspects of sex differences in Parkinson’s disease,” was published in Brain.

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Parkinson’s risk about 1.5 times higher in men

The risk of Parkinson’s disease is not equal between men and women. Studies have consistently found that the incidence of the neurodegenerative disorder is about 1.5 times higher in men, but the reasons for this disparity are not fully known.

It has been proposed that genetic factors may be involved. Specifically, certain genetic variants linked to Parkinson’s could be more prevalent in men than in women. Yet, recent studies have failed to reveal such an association.

Still, genetics could be contributing to disease risk. While a certain variant might be equally prevalent in men or women, it may not have the same biological effects, possibly due to interactions with sex hormones.

In fact, estrogen, a female sex hormone, has been shown to be neuroprotective, and factors such as menstruation and menopause that influence estrogen exposure have also been found to influence Parkinson’s risk or expression.

Thus, “the genes affecting length of estrogen exposure through life … might also affect sex-specific disease risk,” the researchers wrote.

In the study, the scientists aimed to explore that potential relationship by looking for genetic loci, or areas of DNA, that may be associated not only with Parkinson’s risk, but also with sex-specific factors related to estrogen exposure.

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Scientists evaluated data from large genome-wide association studies

To do this, they evaluated data from previous genome-wide association studies in Parkinson’s disease. These large studies are designed to look for genetic alterations that are associated with a particular trait or disease of interest, in this case Parkinson’s, across a large number of people.

Altogether, these studies involved 13,708 people diagnosed with Parkinson’s and 95,282 people who did not have the disease.

The team searched for overlapping genetic loci associated with both Parkinson’s as well as sex-specific traits related to estrogen exposure, namely the age of first menstruation — when estrogen levels increase — and age at menopause, when estrogen levels decline.

Seven loci were shared between Parkinson’s disease and age at first menstruation, and four were shared between Parkinson’s and age at menopause. Of these 11 loci, eight had not been linked before to Parkinson’s.

Genes found in the loci linked to both Parkinson’s and menstruation age were often related to immune function.

Next, the scientists examined sex-specific gene expression, or activity, in brain tissue from Parkinson’s patients and healthy donors.

A total of 142 genes were found to have different activity levels between healthy men and women, whereas men and women with Parkinson’s differed in only 11 genes. None of these genes overlapped with the genetic loci identified in the earlier analyses. Among healthy people, certain known Parkinson’s-related risk genes were differently expressed in men and women.

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Certain variants had opposite effects on gene activity in men and women

Returning to the earlier identified 11 overlapping loci between Parkinson’s and sex-specific factors, certain genetic variants within these loci were predicted to influence the activity of nearby genes in a sex-specific manner. While some influenced gene expression in only one sex, others had opposite effects in the two sexes.

For example, a variant called rs10843831, associated with age at menstruation, was associated with increased activity of the ERGIC2 gene in men, but had the opposite effect in women.

Moreover, variants in a number of genes previously linked to Parkinson’s risk had predicted sex-specific effects on gene activity.

“Further studies are needed to elucidate whether these genes play a role in Parkinson’s disease development and increased incidence in the male population,” the researchers wrote.

Since aging can also influence gene expression in a sex-specific manner, the scientists investigated age-related gene expression changes between men and women in the 11 shared loci.

They found that age-related activity of nine different genes across three loci differed between male and female patients. Again, certain genetic variants in these loci were found to differentially influence the genes’ activity in men and women.

Overall, “we believe that by combining several layers of analysis we were able to highlight genes likely involved in the disease and in the mechanisms leading to an increased incidence in the male population,” the researchers wrote. “However, further functional studies are needed to confirm our findings.”