The APEX (Autism Prenatal Sex Differences) Consortium

APEX is a Cambridge-led research program that explores the links between prenatal biology, sex differences, neurodevelopment and autism.

Males and females can both be autistic but there are on-average differences in the age and likelihood of diagnosis, as well as in how autism is manifested in autistic males and females. The reasons for these differences are both biological and social. APEX focuses on the biological causes of sex differences in autism likelihood and presentation.

APEX is split into three distinct Work Packages, focusing respectively on genetics, prenatal sex steroid hormones, and neurobiological model systems which test these biological factors.

Work Package 1 (Genetics)

Autism is partly the result of genetic differences. In most autistic people this involves a complicated interaction between hundreds of genes. Through three studies we will investigate if there are differences in the genes associated with autism in males and females.

The first study in Work Package 1 (WP1) is a genome-wide association study (GWAS). A GWAS identifies genetic variants that are associated with the likelihood of a particular trait or condition. The GWAS examines common genetic variants associated with autism. These are genes which increase the likelihood of autism but which are found commonly in the general population, in both autistic and non-autistic people. We are investigating if there are differences in the rates of common genetic variants that are seen in autistic males and females.

The second study focuses on rare genetic variants, those present in less than 1 in 1000 people in the population. We will use sequencing data to explore if there are sex differences in rare variants associated with autism. Again, we are investigating if the rate of these rare genetic variants differs between autistic males and females.

Many autistic people, particularly females, are undiagnosed. To take this into account, the third study investigates sex differences in autistic traits across the entire population. We are analysing autistic traits from large, international genetic datasets to investigate if common or rare genetic variants associated with autistic traits differ between the sexes. By studying autistic traits in the entire population, we can produce results that will not be impacted by underdiagnosis.

Work Package 2 (Prenatal Sex Steroid Hormones)

Work Package 2 (WP2) focuses on the regulation and effects of prenatal sex steroid hormones, such as testosterone and estrogen. We focus on these hormones because their levels in the body are affected by biological sex, and because they have a known role in shaping brain development prenatally in both males and females. The levels of these hormones in the womb can also influence some health conditions, such as Polycystic Ovary Syndrome (PCOS) later in life. We are investigating the regulation and the levels of these hormones in autistic and non-autistic people through studies that focus on three separate components of pregnancy: the mother, the infant and the placenta.

Our first study is analysing existing data from the Norwegian Mother and Baby (MoBA) Cohort. This involves analysing sex steroid hormone levels in blood samples collected from the mothers of children later diagnosed as autistic. These were collected during pregnancy as part of routine clinical care. We will compare the levels of steroid hormones in these samples to maternal blood samples collected during the pregnancies of non-autistic children.

Our second study focuses on the placenta, since this organ shows differences between males and female pregnancies in the general population. When a baby is born, researchers in the Tommy’s Maternity Network in Manchester and in the Rosie Hospital in Cambridge will collect the placenta from consenting mothers to study whether there are sex differences in its structure, and to test if genes in the placenta are expressed differently in males to females. We will then investigate if these overlap with differences in the placentas of pregnant women with a family history of autism, compared to those with no family history of autism.

Our third study focuses on the fetus in the womb and its hormonal environment by measuring sex steroid hormone levels in amniotic fluid. We are collaborating with the Meir maternity hospital in Israel to analyse amniotic fluid samples. These are being collected as part of the mother’s routine clinical care. We have previously found that steroid hormone levels in amniotic fluid are associated with autistic traits in toddlers, in both boys and girls. We will now test if this finding can be replicated in an independent population and compare any differences in this relationship in male and female toddlers.

Since the collection of amniotic fluid carries a small risk of miscarriage, we will only use data from mothers who have already chosen to have amniocentesis performed for medical reasons. This means no amniotic fluid will be collected purely for research purposes, and nor will mothers be recruited based on any specific criteria, including a family history of autism.

Work Package 3 (Model Systems)

Work Package 3 (WP3) is investigating the link between sex differences and autism using induced pluripotent stem cells (iPSCs) to model and understand early neurodevelopment. iPSCs are created by taking a cell from the body (we use a hair follicle), reversing it back to being a stem cell which is pluripotent (a cell that could become any type of cell or tissue in the body) and then programming it to develop into a nerve cell (neuron) outside the body. We will compare iPSCs derived from autistic males and females, by observing their response to sex steroid hormones or by looking at sex-linked genes in these.

WP3 experiments are studying how proteins expressed by genes associated with autism identified in WP1 are altered by sex steroid hormones. These studies are conducted in collaboration with the Medical Research Council’s Laboratory for Molecular Biology (MRC LMB) and King’s College London. Our APEX partners in Exeter University are also using post-mortem brain tissue to test if the same genes and proteins which respond to sex steroid hormones are seen in autistic people’s brains, and how these compare to the gene expression levels observed in placentas from women with a family history of autism (WP2).

Impact

The APEX program will deepen our understanding of autism, why autism may manifest differently in males and females, and why autism is diagnosed less frequently in females. Together, these studies will help us understand the role that prenatal sex steroid hormones play in autism, particularly during brain development.

APEX studies may also have relevance for understanding why autistic women experience higher rates of hormone conditions such as PCOS and pregnancy complications. This could help inform future research to provide more effective treatment for these conditions.

Community Engagement

Each study within APEX is conducting its own community engagement. For WP1, we have completed an extensive consultation (including focus groups, webinars, surveys and an online discussion platform) with the autism community about genetics research in autism, with a particular focus on bioethical concerns.

For WP2, our engagement included designing a data sharing policy for the amniocentesis study. We consulted 46 members of the autism community, 29 of whom were autistic, and engagement involved a UK-based survey, an Israel-based survey, and a UK-based focus group. In addition, we consulted 10 people (including pregnant mothers and autistic people) in Israel about the study procedures, to make sure that participants find the study safe and comfortable.

For WP3, we will conduct a survey and hold focus groups about the topic of using of model systems in autism research. Any new data collected during these new studies will only be shared with researchers outside of the APEX consortium following approval by the Data Sharing Committee, which will include both researchers and autistic people.

All of the studies in the APEX program are being conducted purely to understand autism better. We are specifically interested in understanding the different development trajectories and health needs of autistic males and females. We do not support developing a prenatal test for autism, as we oppose any attempt to prevent or cure autism, although we do support treatment for co-occurring health conditions that cause distress, where these are desired by autistic people themselves. These policies are based on the ARC Values and our Community Engagement Commitment.

Staff

Principal Investigator

Program Coordinator

Staff (WP1)

Staff (WP2)

Staff (WP3)

APEX Associates

Funders

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