Research has documented a robust male sex bias in attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and Tourette syndrome (TS).
Amongst 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 focus on 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
The male sex bias in lots of neurodevelopmental disorders (NDD) stays largely unexplained. The “female protective effect” (FPE) has been recommend as one potential explanation, mediated by aspects similar to differences in physiology, sex hormones, and so forth.
Genetic disruptions of Chr X have been widely researched, and a number of other genes have been linked to X-linked monogenic disorders mainly affecting males. Klinefelter syndrome and Turner syndrome are two such risks related to Chr X.
By way of existing research on “idiopathic” types of TS, ASD, and ADHD, genome- or exome-wide studies haven’t been very effective in detecting risk genes on Chr X.
In regards to the study
The important thing to this evaluation was the provision of good-quality data compiled from different sources. For ASD, whole-exome sequencing (WES) data was obtained from 2058 families within 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. Moreover, WES was performed for twenty-four recent 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. Moreover, 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 identical family. This led to excluding 123 female SSC siblings and 647 male ASD probands.
The WES data, obtained from female and male ASD probands, was used to detect maternally inherited and rare variants on Chr X. 746 male siblings from the SSC were in comparison with 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 within the Chr X non-PAR that persistently segregated with risk. The outcomes were then replicated within 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 evaluation has also been replicated in TS and ADHD datasets.
The current study confirmed a very important result documented in prior research, namely, ASD risk in males will be influenced by LGD mutations on Chr X non-PAR.
The enrichment of rare Mis3 variants couldn’t be identified, which was a degree of deviation from previous studies. The damaging variants remained present throughout the risk-enriched regions (RERs) and weren’t driven by population stratification. It may be replicated in a big 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 means that damaging variants within the RERs mainly contribute to male-specific risk.
In sum, the findings on the underlying biology of TS, ASD, and ADHD motivate additional exploration of genetic risk on Chr X. This must also be carried out in other NDDs with a male sex bias.
Future research should aim to analyze 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, due to this fact, based on a hard and fast window size. Moreover, the families considered here had a minimum of three male children, which could have biased the outcomes.