How rare and common risk variation jointly affect liability for autism spectrum disorder

Abstract Background Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. Methods To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth “burden”), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD (“PDV carriers”); ASD subjects who do not (“non-carriers”); and unaffected subjects who are assumed to be non-carriers. Results Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. Limitations Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. Conclusions Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk.

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How rare and common risk variation jointly affect liability for autism spectrum disorder

10.1101/2020.10.27.20220095 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lambertus Klei ◽

Lora Lee McClain ◽

Behrang Mahjani ◽

Klea Panayidou ◽

Silvia De Rubeis ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Genetic Variation ◽

Rare Variants ◽

Population Level ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Common Genetic Variation ◽

Control Subjects ◽

Mutation Carriers ◽

Risk Variants

AbstractBackgroundGenetic studies have implicated rare and common variation in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study.MethodsTo explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variation (Simons Simplex Collection and Population-Based Autism Genetics & Environment Study). We analyzed data from 3,011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3,011 subjects matched for ancestry to ASD subjects; and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk for ASD (henceforth burden), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a rare damaging variant implicated in risk for ASD (mutation carriers); ASD subjects who do not (non-carriers); and unaffected subjects, who are assumed to be non-carriers.ResultsBurden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For mutation carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability.LimitationsOnly 258 ASD subjects were known mutation carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific mutations or genes. Also, a small fraction of subjects that are categorized as non-carriers could be mutation carriers.ConclusionsLiability arising from common and rare risk variation likely combine additively to determine risk for any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare mutation affecting risk.

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Involvement of the 14-3-3 Gene Family in Autism Spectrum Disorder and Schizophrenia: Genetics, Transcriptomics and Functional Analyses

Journal of Clinical Medicine ◽

10.3390/jcm9061851 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1851

Author(s):

Bàrbara Torrico ◽

Ester Antón-Galindo ◽

Noèlia Fernàndez-Castillo ◽

Eva Rojo-Francàs ◽

Sadaf Ghorbani ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Psychiatric Disorders ◽

Rare Variants ◽

Neurological Diseases ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Risk Variants ◽

Whole Exome ◽

Target Binding ◽

Functional Analyses

The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.

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A systematic review of common genetic variation and biological pathways in autism spectrum disorder

BMC Neuroscience ◽

10.1186/s12868-021-00662-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Diego Alejandro Rodriguez-Gomez ◽

Danna Paola Garcia-Guaqueta ◽

Jesús David Charry-Sánchez ◽

Elias Sarquis-Buitrago ◽

Mariana Blanco ◽

...

Keyword(s):

Systematic Review ◽

Autism Spectrum Disorder ◽

Genetic Variation ◽

Postsynaptic Membrane ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Cell Junction ◽

Biological Processes ◽

Common Genetic Variation ◽

Kegg Pathway Database

Abstract Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD. Results 177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction. Conclusions Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism.

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Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽

10.3390/genes12071053 ◽

2021 ◽

Vol 12 (7) ◽

pp. 1053

Author(s):

Jasleen Dhaliwal ◽

Ying Qiao ◽

Kristina Calli ◽

Sally Martell ◽

Simone Race ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Rare Variants ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Compound Heterozygous ◽

Variable Effect ◽

Gabaergic Neurotransmission ◽

High Heritability ◽

Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

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Gut Microbiome-Based Analysis of Lipid A Biosynthesis in Individuals with Autism Spectrum Disorder: An In Silico Evaluation

Nutrients ◽

10.3390/nu13020688 ◽

2021 ◽

Vol 13 (2) ◽

pp. 688

Author(s):

Abdulkadir Yusif Maigoro ◽

Soojin Lee

Keyword(s):

Autism Spectrum Disorder ◽

Gut Microbiome ◽

In Silico ◽

Lipid A ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Synthesis Rate ◽

Special Focus ◽

Control Subjects ◽

Gastrointestinal Problems

The link between autism spectrum disorder (ASD) and the gut microbiome has received much attention, with special focus on gut–brain-axis immunological imbalances. Gastrointestinal problems are one of the major symptoms of ASD and are thought to be related to immune dysregulation. Therefore, in silico analysis was performed on mined data from 36 individuals with ASD and 21 control subjects, with an emphasis on lipid A endotoxin-producing bacteria and their lipopolysaccharide (LPS) metabolic pathways. Analysis of enzyme distribution among the 15 most abundant genera in both groups revealed that almost all these genera utilized five early-stage enzymes responsible for catalyzing the nine conserved lipid A synthesis steps. However, Haemophilus and Escherichia, which were significantly more abundant in individuals with ASD than in the control subjects, possess a complete set of essential lipid A synthesis enzymes. Furthermore, the 10 genera with the greatest increase in individuals with ASD showed high potential for producing late-stage lipid A products. Collectively, these results suggested that the synthesis rate of immunogenic LPS end products is likely to increase in individuals with ASD, which may be related to their gastrointestinal symptoms and elevated inflammatory conditions.

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