Research on Sex, Gender, and Neurodevelopment in the Michaelson Lab

Our goal is to better understand the molecular and genetic interplay between sex, gender, and neurodevelopment. Sex is a well-established factor that has a profound effects on neurodevelopment and health broadly. For instance, autism is highly male-biased (4:1) and anorexia nervosa is highly female-biased (8:1). What is less understood is whether a continuous (rather than binary) view of sex and gender can yield additional biological insights into these and related conditions, and more generally into how the brain develops. Societal changes over the past several decades (and that are still ongoing) have cast a spotlight on the fact that sex and gender can be more nuanced than simple binary indicators.These realizations are now penetrating into the scientific process, and as we seek for greater understanding of our own biology, it has become clear that a more nuanced treatment of sex and gender can be useful in many lines of research. Autism specifically calls for a more nuanced understanding of gender. Recent research has revealed there is an enrichment of gender diversity in autistic samples compared to the general population. Likewise, general population samples of individuals identifying as transgender or non-binary are more likely to have clinically relevant levels of autistic traits. Our own research has found that masculinity, as reflected in the structure of the face of both males and females, is associated with increased symptom severity and increased reports of poor social functioning in individuals with autism. These findings and observations may be related, or they might function independent of one another. In either case, they suggest an important role for sex and gender in our understanding of autism and neurodevelopment broadly. To make progress in this research, we are partnering with members of the LGBTQ community because of their rich diversity along the axes of sex and gender. It is important to emphasize that just as the examples of sex bias in autism and anorexia do not "pathologize" being a male or a female, respectively, our research does not pathologize gender diversity. While our chief goal is to better understand the role of sex and gender in neurodevelopment, it is possible that we will also make new discoveries about the general biological basis of sex and gender. Because these are fundamental aspects of the human experience, we are both tremendously excited by this research opportunity, but also keenly aware of its ramifications and risks.

Ultimately, we hope to advance the health of gender diverse people through a greater understanding of how genetic factors interact with gender diversity in determining health outcomes.

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Role of the LGBTQ+ community in our research process

Role of the LGBTQ+ community in our research process

With the rapid expansion of genomic technologies, it is inevitable that research will be conducted into the genetic basis of sexual orientation and gender identity. In fact, much of this research is already in progress at institutions around the world. A recent genetic study in over 400,000 participants identified genetic factors significantly associated with same-sex sexual behavior [4]. It is important to us that this research be conducted in close coordination with stakeholders in the LGBTQ community so that research plans take into account their suggestions, concerns, and anticipated risks. Specifically, our research plan provides for the following:

1. We have established a community advisory council (CAC) composed of neurodiverse, LGBTQ+ individuals in which we meet annually.
2. Our research team includes scientists who are LGBTQ+
3. We work closely with and solicit input from healthcare professionals who serve the LGBTQ+ community
4. The LGBTQ+ community is well-represented among our scientific collaborators on this project
5. We conducted a survey in N = 768 individuals, many who are LGBTQ+, and asked their opinions about genetic research in this area.  We analyzed the data from this study, and the resulting publication can be found here [5]. The input we received in our survey, as well as the regular input we receive from our community advisory council and collaborators are crucial to guiding our research in many ways, specifically in communication of results and in assessing the potential value and risks of future research. However, it is also important to emphasize that we have no agenda. We form hypotheses based on current knowledge, we collect data, and we analyze that data to determine whether it tends to support or refute our hypotheses. We strongly support our partners in the LGBTQ community, and the first priority in our relationship is to ensure that voices are heard and risks are minimized. At the same time, as scientists, the integrity of our process is vital,and we will not coerce our findings into conclusions that we think will satisfy one community or another.

 

Our research communication policies

Our community advisory council (CAC) is made up of members from the stakeholder communities (in this case, LGBTQ+ and neurodiverse).  One purpose of the CAC is to help us anticipate how the community will respond to the results of our research, before it is published. By previewing results to the CAC, we can develop messaging that is scientifically accurate, but that also reduces risks and addresses concerns raised.  Because journalists and science writers are a critical link in the chain of communicating science back to the general public, we will also hold a focus group with these professionals. This will address the challenges of communicating results that have a risk of misuse or abuse, and will lead to the development of a plan to ensure accurate communication of results, specifically on this topic.  We also update our website with results of these studies, written in a layperson-friendly way, so that the public has a primary, authoritative source that presents the findings, as well as the limitations, of our studies.

Possible benefits of our research

Although many from the LGBTQ community do not look to biology to validate their experiences, if our research results in additional support for a biological basis of diversity in gender identity and sexuality, that may lead to increased acceptance among non-LGBTQ individuals. In addition, an increased understanding of the biological basis for diversity in sex and gender would contribute to better and more individualized health care for members of the LGBTQ community. With regard to the autism community, our research aims to better understand the biology of neurodevelopment so that therapeutic options can be better tailored to individual needs.  Some members of the autism community are rightly concerned about outsiders confusing the identity-oriented aspects of autism (e.g., personality and preferences) with the disabling aspects of autism (e.g., seizures, sleep and gastrointestinal problems, self-harm, etc.). Our goal in better understanding autism is to enable therapeutic options that focus on the disabling aspects, and not on the identity aspects.

Possible risks of our research and the steps we are taking to mitigate the risk

It is possible that in the course of our research, we may discover that certain genetic variants are linked to both neuropsychiatric conditions and either sexual orientation or gender identity. Geneticists call this phenomenon pleiotropy, which means that a genetic variant affects multiple traits. Pleiotropy is well-established phenomenon and does not imply a value statement on the linked traits. On a larger scale, a similar concept called genetic correlation can quantify how much of a genetic basis two different traits share. The genetic study of same-sex sexual behavior in over 400,000 individuals did find an overlap of same-sex sexual behavior genetic factors with neuropsychiatric genetic factors [4]. For instance, previous research has found a positive genetic correlation between risk for autism and educational attainment [6], as well as risk for schizophrenia and creativity [7]. These examples demonstrate that sometimes traits that are generally seen as a liability share a basis with traits that are considered desirable. Consequently, just because two traits share a genetic basis does not automatically imply a value judgment through” guilt by association”. However, we recognize that these kinds of nuances are often lost in the process of communicating science to the public. In some cases, the nuance is willfully removed to promote a particular agenda. As outlined above, our goal is to mitigate this possibility through a proactive approach to science communication that involves community stakeholders. We cannot guarantee that the results of our research, once in the hands of the public, will remain free of biased interpretation. However, because this area of research is ongoing at institutions around the world, this reality exists whether or not we participate. We hope that by making a research contribution that is both scientifically rigorous and informed by community perspectives, we can minimize the potential risks inherent in this line of inquiry.

 

Our research results so far

1. 1. Community attitudes on genetic research of gender identity, sexual orientation, and mental health

Published July 2020 in PLOS One

Link: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235608

In this study, we surveyed 768 individuals, many who were LGBTQ+ stakeholders, and asked their opinions about genetic research in gender identity, sexual orientation, and mental health. Our main findings were:

1. 1. 1. Opinions were heterogenous (i.e. no consensus). An overall positive view of mental health research was the most important factor that was indicative of a positive endorsement of this research. 2. Individuals who were the least tolerant of the LGBTQ+ community said that scientific research uncovering a biological basis of sexual and gender diversity would change their view to be more accepting. 3. Variation in masculinity and femininity is expressed by cisgender people, not just the LGBTQ+ community (see below).

1. 2. Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts

Published June 2021 in Molecular Autism

Link: https://molecularautism.biomedcentral.com/articles/10.1186/s13229-021-00450-w

An overview of the study is described below.

Our main findings were:

1. 1. 1. Higher polygenic scores for testosterone are associated with higher digit ratio masculinity
      2. Lower polygenic scores for sex hormone binding globulin are associated with higher facial masculinity
      3. Higher polygenic scores for testosterone and lower polygenic scores for sex hormone binding globulin are associated with poorer social functioning in autistic children.

 

1. 3. Genetic potentiators of cognitive performance are associated with increased divergence from gendernorms

Not published yet, but a preprint (not peer reviewed) can be found here:

https://doi.org/10.1101/2021.11.22.21266696

Our main findings were:

1. 1. 1. Higher polygenic scores for cognitive performance and same-sex sexual behavior were correlated with greater gender diversity.
      2. Greater gender diversity was correlated with poorer mental health. After controlling for the effects of genetic liability, we found the correlations only moderately attenuated, suggesting that not genetic factors, but environmental factors like discrimination, play a substantial role in worse mental health for gender diverse people.

4. A. Ganna, K. J. H. Verweij, M. G. Nivard, R. Maier, R. Wedow, A. S. Busch, A. Abdellaoui, S. Guo, J. F. Sathirapongsasuti, null null, P. Lichtenstein, S.Lundstr¨om, N. L˚angstr¨om, A. Auton, K. M. Harris, G. W. Beecham, E. R. Martin, A. R. Sanders, J. R. B. Perry, B. M. Neale, and B. P. Zietsch, “Large-scale gwas reveals insights into the genetic architecture of same-sex sexual behavior,” Science, vol. 365, no. 6456, p. eaat7693, 2019.
5. T. R. Thomas, D. Hofammann, B. G. McKenna, A. IR van der Miesen, M. A. Stokes, P. Daniolos, and J. J. Michaelson, “Community attitudes on genetic research of gender identity, sexual orientation, and mental health,” Plos one, vol. 15, no. 7, p. e0235608, 2020.
6. J. Grove, S. Ripke, T. D. Als, M. Mattheisen, R. K. Walters, H. Won, J. Pallesen, E. Agerbo, O. A. Andreassen,

R. Anney, et al., “Identification of common genetic risk variants for autism spectrum disorder,” Nature genetics, vol. 51, no. 3, pp. 431–444, 2019.

7. R. A. Power, S. Steinberg, G. Bjornsdottir, C. A. Rietveld, A. Abdellaoui, M. M. Nivard, M. Johannesson, T. E. Galesloot, J. J. Hottenga, G. Willemsen, et al., “Polygenic risk scores for schizophrenia and bipolar disorder predict creativity,” Nature neuroscience, vol. 18, no. 7, pp. 953–955, 2015.