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Last Posted: Sep 29, 2022
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Identification of shared and differentiating genetic architecture for autism spectrum disorder, attention-deficit hyperactivity disorder and case subgroups.
Mattheisen Manuel et al. Nature genetics 2022 9

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are highly heritable neurodevelopmental conditions, with considerable overlap in their genetic etiology. We dissected their shared and distinct genetic etiology by cross-disorder analyses of large datasets. We identified seven loci shared by the disorders and five loci differentiating them. All five differentiating loci showed opposite allelic directions in the two disorders and significant associations with other traits.

Diverse mutations in autism-related genes and their expression in the developing brain
Nature Genetics, August 18, 2022

Across >150,000 individuals, we identified hundreds of genes associated with autism spectrum disorder (ASD) and atypical neurodevelopment. Most ASD-related genes were also associated with developmental delay. However, increased mutation rates in ASD and shared genetic risk with schizophrenia was observed for some genes, many of which are enriched in developing neurons.

Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
JM Fu et al, Nature Genetics, August 18, 2022

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR)?=?0.001 (185 at FDR?=?0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk.

Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
X Zhou et al, Nature Genetics, August 18, 2022

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P?<?2.5?×?10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect

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