Compared to men, women and people who are non-binary, not identifying exclusively as either men or women, have higher rates of prevalent health conditions, ranging from asthma to heart attack, and are more likely to develop adverse drug reactions.
While many factors may contribute to these wide variations in health, among the most important was, until recently, one of the least studied — the sex chromosomes. Turns out, variations in genes carried on the X and Y chromosomes can profoundly affect complex health conditions including diabetes, heart disease and depression.
“It’s not that males and females have different genes that are leading to those diseases, it’s that those genes are interacting with other (social and environmental) factors in different ways,” said Lea Davis, PhD, associate professor in the Division of Genetic Medicine at Vanderbilt University Medical Center.
“Understanding how these factors differ by sex and across people of all gender identities is going to be a really important piece of the puzzle,” Davis said.
Davis and longtime colleagues Ekaterina (Katya) Khramtsova, PhD, and Barbara Stranger, PhD, are among seven authors of a paper published May 11 in the journal Cell that outlines “best practices” for evaluating the impact of both sex and gender on human health.
The three women began working together nearly a decade ago at the University of Chicago to understand how sex modifies the genetic risk for disease.
“For a long time, we felt we were working in isolation,” Davis said. “There weren’t that many other people, frankly, who were interested in looking at sex differences.”
For example, many applications of the genome-wide association study (GWAS), which rapidly scans a person’s DNA for genetic variations associated with a particular disease or drug response, have excluded the X and Y chromosomes.
While in the past it has been technically difficult to include X and Y chromosomes in these analyses, “there are many methods out there now for doing that work,” Davis said. “There’s really no excuse for not (including them) anymore.”
It is becoming clear from studies of hundreds of thousands of individuals that sex is a very complicated biological variable.
“Sex can be defined using lots of different markers, so it’s really not one thing,” Davis said. “It’s a combination of multiple biological and environmental factors that contribute to the presentation that we lump together and call sex.”
Traditionally, when a baby is born, whoever is attending the delivery assigns the child’s sex based on visual examination. “We think of that as being a binary construct — you’re either male or female,” Davis said. “But in reality, ambiguity is not uncommon.”
In some cases, a baby who appears to be female at birth may have an XY chromosome pair and will develop male attributes when puberty hits. Others may have only one X and no Y chromosome or three X chromosomes. “There’s a lot of variation out there,” Davis said.
In the past, people with aneuploidies, extra or missing chromosomes, were excluded from genetic studies.
Future studies should include not only people with sex chromosome aneuploidies and differences of sex development, but also intersex and transgender individuals, the researchers wrote. This information will be crucial to “disentangling” the chromosomal, genetic, hormonal and environmental factors that affect disease risk and treatment outcomes for everyone.
“A better understanding of basic biological differences, as well as gendered environmental differences, is key for both understanding disease and developing efficacious and safe therapies,” the researchers concluded. “Including these dimensions will improve health outcomes for all people.”
Khramtsova is a principal scientist at the Janssen Pharmaceutical Companies of Johnson & Johnson, and Stranger is associate professor of Pharmacology at Northwestern University. Other co-authors: Melissa Wilson, PhD, Arizona State University, Joanna Martin, PhD, Cardiff University, Stacey Winham, PhD, Mayo Clinic, and Karen He, PhD, Janssen.
The research was supported by a grant from the Brain & Behavior Research Foundation and by National Institutes of Health grants GM124827, CA229618, and HG011405. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
