ASD and ADHD have a similar burden of rare protein-truncating variants

Fk, Satterstrom; Rk, Walters; Singh, Tarjinder; Em, Wigdor; Lescai, Francesco; Demontis, Ditte; Ja, Kosmicki; Grove, Jakob; Stevens, Christine; Bybjerg‐Grauholm, Jonas; Bækvad‐Hansen, Marie; Ds, Palmer; Jb, Maller; Nordentoft, Merete; Mors, Ole; Eb, Robinson; Dm, Hougaard; Tm, Werge; Pb, Mortensen; Bm, Neale; Børglum, Anders D.; Daly, Mark J.

doi:10.1101/277707

Cited by 32 publications

(41 citation statements)

References 29 publications

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“…We collected de novo variants identified in (47) : 561), 6,430 ASD probands, and 2,179 unaffected controls from the Autism Sequencing Consortium (25). We also utilized a previously published dataset of variants in 8,437 cases with ASD and/or attention-deficit/hyperactivity disorder and 5,214 controls from the Danish Neonatal Screening Biobank (48). In this analysis, we analyzed pLoF variants identified in highly constrained genes (first LOEUF decile) with a combined total allele count of ≤ 10 in cases and controls.…”

Section: De Novo and Rare Variant Analysismentioning

confidence: 99%

Transcript expression-aware annotation improves rare variant discovery and interpretation

Cummings

Karczewski

Kosmicki

et al. 2019

Preprint

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The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expressionbased annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

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Section: De Novo and Rare Variant Analysismentioning

confidence: 99%

Transcript expression-aware annotation improves rare variant discovery and interpretation

Cummings

Karczewski

Kosmicki

et al. 2019

Preprint

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“…S1; Table S1). Of these, 17,462 samples were either newly 14 sequenced by our consortium (6,197 samples: 1,908 probands with parents; 274 ASD cases; 25 15 controls) or newly incorporated (11,265 samples: 416 probands with parents;4,811 ASD cases 16 and 5,214 controls from the Danish iPSYCH study (Satterstrom et al, 2018)). 17 18 From this cohort, we identified a set of 9,345 rare de novo variants in protein-coding exons 19 (allele frequency ≤ 0.1% in our dataset as well as in the non-psychiatric subsets of the reference 20 databases ExAC and gnomAD, with 63% of probands and 59% of unaffected offspring carrying 21 at least one such rare coding de novo variant-4,073 out of 6,430 and 1,294 out of 2,179, 22 respectively; Table S2; Fig.…”

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confidence: 99%

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Fk¹,

Ja²,

Wang³

et al. 2018

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SummaryWe present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total samples, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

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“…For example, CNVs in ASD and ADHD indicate similar biological pathways 19 , and both disorders carry a similar burden of rare protein-truncating variants, implicating shared genes 34 . Despite these biological commonalities, the assignment of clinical diagnoses to patients comorbid for ASD and ADHD symptomatology has been, until the introduction of the Diagnostic Statistical Manual of Mental Disorders 5th edition (DSM-5) 35 , less formalised.…”

Section: Discussionmentioning

confidence: 99%

Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

Verhoef

Grove

Shapland

et al. 2019

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Insight into shared polygenetic architectures affects our understanding of neurodevelopmental disorders. Here, we investigate evidence for pleiotropic mechanisms that may explain the comorbidity between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). These complex neurodevelopmental conditions often co-occur, but differ in their polygenetic association patterns, especially with educational attainment (EA), showing discordant association effects. Using multivariable regression analyses and existing genome-wide summary statistics based on 10,610 to 766,345 individuals, we demonstrate that EA-related polygenic variation is shared between ASD and ADHD. We show that different combinations of the same ASD and ADHD risk-increasing alleles can simultaneously re-capture known ASD-related positive and ADHD-related negative associations with EA. Such patterns, although to a lesser degree, were also present for combinations of other psychiatric disorders. These findings suggest pleiotropic mechanisms, where the same polygenic sites can encode multiple independent, even discordant, association patterns without involving distinct loci, and have implications for cross-disorder investigations.

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ASD and ADHD have a similar burden of rare protein-truncating variants

Cited by 32 publications

References 29 publications

Transcript expression-aware annotation improves rare variant discovery and interpretation

Transcript expression-aware annotation improves rare variant discovery and interpretation

Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism

Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

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