Discontinuity in the genetic and environmental causes of the intellectual disability spectrum

Reichenberg, Abraham; Cederlöf, Martin; McMillan, Andrew; Trzaskowski, Maciej; Kapara, Ori; Fruchter, Eyal; Ginat, Karen; Davidson, Michael; Weiser, Mark; Larsson, Henrik; Plomin, Robert; Lichtenstein, Paul

doi:10.1073/pnas.1508093112

Cited by 95 publications

(86 citation statements)

References 48 publications

(63 reference statements)

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“…Interestingly, findings were different for the most severe form of ID (profound ID) which did not show familial co-aggregation with ADHD. This finding is in keeping with the view that ID mainly lies at one end of a multi-factorial, polygenic continuum of intellectual ability whereas profound ID is etiologically distinct and qualitatively different from the rest of the IQ spectrum and mild-moderate ID 7 . This discontinuity appears to apply to the familial co-aggregation with ADHD and might be explained by rare causes including genetic syndromes (e.g.…”

supporting

confidence: 88%

Intellectual Disability and Attention-Deficit/Hyperactivity Disorder: What Does the Clinical and Genetic Overlap Mean for Practice and Research?

Thapar

2017

Journal of the American Academy of Child & Adolescent Psych

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supporting

confidence: 88%

Intellectual Disability and Attention-Deficit/Hyperactivity Disorder: What Does the Clinical and Genetic Overlap Mean for Practice and Research?

Thapar

2017

Journal of the American Academy of Child & Adolescent Psych

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“…Family studies yield high heritability estimates in ASD (Yip et al, 2018), but comparable 6 estimates of heritability in severe NDD are lower (Reichenberg et al, 2016). Consistent with 7 these observations, exome studies identify a higher frequency of disruptive de novo variants in 8 severe NDD than in ASD (Deciphering Developmental Disorders, 2017).…”

Section: Relationship Of Asd Genes With Gwas Signal 18mentioning

confidence: 80%

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

Fk¹,

Ja²,

Wang³

et al. 2018

Preprint

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346

702

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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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“…While genome-wide studies using microarrays and exome sequencing have identified a prominent role of de novo copy number variations (CNVs), INDELs and single nucleotide variants in mostly severe ID with reported diagnostic yields of 13%-42%, their role in mild ID is less studied but expected to have a less prominent role 3,4 . Intriguingly siblings of mild ID individuals have low IQ compared to the general population whereas the IQ of siblings of severe ID individuals do not differ from the general population 5 . This suggests that mild ID represents a low extreme in a normal distribution of IQ, while severe ID is a distinct condition with different etiology 5 .…”

Section: Introductionmentioning

confidence: 87%

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

Kurki

Saarentaus

Pietiläinen

et al. 2018

Preprint

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The contribution of de novo and ultra-rare genetic variants in severe and moderate intellectual disability (ID) has been extensively studied whereas the genetic architecture of mild ID has been less well characterized. To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals.We show that rare damaging variants in genes known to be associated with cognitive defects are observed more often in severe (27%) than in mild ID (13%) patients (p-value: 7.0e-4). We further observed a significant enrichment of protein truncating variants in loss-of-function intolerant genes, as well as damaging missense variants in genes not yet associated with cognitive defects (OR: 2.1, pvalue: 3e-8). For the first time to our knowledge, we show that a common variant polygenic load significantly contributes to all severity forms of ID. The heritability explained was the highest for educational attainment (EDU) in mild ID explaining 2.2% of the heritability on liability scale. For more severe ID it was lower at 0.6%.Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria. The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection.

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Discontinuity in the genetic and environmental causes of the intellectual disability spectrum

Cited by 95 publications

References 48 publications

Intellectual Disability and Attention-Deficit/Hyperactivity Disorder: What Does the Clinical and Genetic Overlap Mean for Practice and Research?

Intellectual Disability and Attention-Deficit/Hyperactivity Disorder: What Does the Clinical and Genetic Overlap Mean for Practice and Research?

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

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

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