Research has documented a strong male sex bias in attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette syndrome (TS).
Among males, the hemizygous nature of chromosome X (Chr X) has been a known vulnerability factor. Still, the characterization of rare genetic variation in Chr X has not been conducted in large-scale studies.
Addressing this gap in research, a recent Nature Communications study exploited informative recombinations seen in simplex ASD families to highlight the risk-prone regions on Chr X.
Study: Rare X-linked variants carry predominantly male risk in autism, Tourette syndrome, and ADHD. Image Credit: Elms Art/Shutterstock.com
Background
The male sex bias in many neurodevelopmental disorders (NDD) remains largely unexplained. The “female protective effect” (FPE) has been put forward as one potential explanation, mediated by factors such as differences in physiology, sex hormones, and so on.
Genetic disruptions of Chr X have been widely researched, and several genes have been linked to X-linked monogenic disorders mainly affecting males. Klinefelter syndrome and Turner syndrome are two such risks associated with Chr X.
In terms of existing research on “idiopathic” forms of TS, ASD, and ADHD, genome- or exome-wide studies have not been very effective in detecting risk genes on Chr X.
About the study
The key to this analysis was the availability of good-quality data compiled from different sources. For ASD, whole-exome sequencing (WES) data was obtained from 2058 families in the Simons Simplex Collection (SSC).
This included 1,597 quartets and 461 trios. For TS, WES data from previous research were reused. Which included 546 TS trios with male probands. Additionally, WES was performed for 24 new trios using the xGen Exome Research Panel (IDT).
With regard to ADHD, data were collected for 341 male probands from the UK. Child and Adolescent Psychiatry was used to shortlist participants aged between 5 and 18 years.
The diagnosis of ADHD was confirmed using the Child and Adolescent Psychiatric Assessment’s parent version. Finally, for Epileptic encephalopathy (EE), WES data were obtained for 223 male probands from the Epi4K consortium.
Samples that showed unexpected relationships based on a custom script were excluded. Additionally, if an inconsistent sex was deduced from the sex chromosome single nucleotide polymorphisms (SNPs), the sample was excluded.
After quality control, the sample included 332 ADHD male probands, 570 male TS probands, 223 EE male probands, 1,680 SSC siblings, and 1975 ASD probands.
Further steps were taken to mitigate bias stemming from proband-siblings from the same family. This led to excluding 123 female SSC siblings and 647 male ASD probands.
Key findings
The WES data, obtained from male and female ASD probands, was used to detect maternally inherited and rare variants on Chr X. 746 male siblings from the SSC were compared to 1,014 male ASD probands. By doing so, the overrepresentation of maternally inherited rare Chr X non-PAR LGD variants was confirmed in males.
Genotyping data from SSC families was obtained for those with multiple male children to detect regions in the Chr X non-PAR that persistently segregated with risk. The results were then replicated in the SPARK ASD cohort.
Subsequently, (MAGEC3), an exome-wide significant ASD risk gene, was highlighted by combining 11,391 and 1661 SPARK and SSC male probands, respectively. This analysis has also been replicated in TS and ADHD datasets.
The present study confirmed an important result documented in prior research, namely, ASD risk in males can be influenced by LGD mutations on Chr X non-PAR.
The enrichment of rare Mis3 variants could not be identified, which was a point of deviation from previous studies. The damaging variants remained present within the risk-enriched regions (RERs) and were not driven by population stratification. It could also be replicated in a large independent ASD cohort.
Risks stemming from rare hemizygous damaging variants in TS and ADHD were also identified. No enrichment was noted in female ASD patients, which implies that damaging variants in the RERs mainly contribute to male-specific risk.
Conclusions
In sum, the findings on the underlying biology of TS, ASD, and ADHD motivate additional exploration of genetic risk on Chr X. This should also be carried out in other NDDs with a male sex bias.
Future research should aim to investigate and characterize the overlap between other contributors to risk and resilience and this male-specific risk factor.
One limitation of the study was the small sample size, which led to limited power in defining RERs. RERs were, therefore, based on a fixed window size. Additionally, the families considered here had at least three male children, which could have biased the results.
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