Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

Franić, Sanja; Groen-Blokhuis, Maria M.; Dolan, Conor V.; Kattenberg, Mathijs; Pool, René; Xiao, Xiangjun; Scheet, Paul; Ehli, Erik A.; Davies, Gareth E.; Sluis, Sophie van der; Abdellaoui, Abdel; Hansell, Narelle K.; Martin, Nicholas G.; Hudziak, James J.; Beijsterveldt, Catharina E. M. van; Swagerman, Suzanne C.; Pol, Hilleke E. Hulshoff; Geus, Eco J. C. de; Bartels, Meike; Ropers, Hans‐Hilger; Hottenga, Jouke Jan; Boomsma, Dorret I.

doi:10.1038/ejhg.2015.3

Cited by 17 publications

(18 citation statements)

References 45 publications

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“…We also identified a LoF mutation in TMEM135, previously been reported in the large Iranian NS-ARID cohort by Najmabadi et al, 2011 (in which a missense mutation, Cys228Ser was reported) 11 , and in Wright et al, 2014 (missense) 46 , also as a quantitative trait locus for intelligence 47 .…”

Section: Homozygous Loss-of-function Mutationssupporting

confidence: 76%

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Harripaul

Vasli

Mikhailov

et al. 2016

Preprint

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4Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7, and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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Section: Homozygous Loss-of-function Mutationssupporting

confidence: 76%

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Harripaul

Vasli

Mikhailov

et al. 2016

Preprint

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“…Thus, although linkage and association studies have identified strong evidence of a genetic influence, many rarer variants with aetiological relevance may be overlooked because they will not be captured by single nucleotide polymorphism (SNP) arrays, or do not reach stringent significance parameters. Recent findings indicate that the boundary between common traits and monogenic forms of disorder may be less defined than previously thought2526. Accordingly, with advances in molecular technologies, examples can be drawn from the literature of rare or private high-penetrance variants that contribute to certain forms of speech and language deficits24.…”

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confidence: 99%

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

Chen

Reader

Hoischen

et al. 2017

Sci Rep

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A significant proportion of children have unexplained problems acquiring proficient linguistic skills despite adequate intelligence and opportunity. Developmental language disorders are highly heritable with substantial societal impact. Molecular studies have begun to identify candidate loci, but much of the underlying genetic architecture remains undetermined. We performed whole-exome sequencing of 43 unrelated probands affected by severe specific language impairment, followed by independent validations with Sanger sequencing, and analyses of segregation patterns in parents and siblings, to shed new light on aetiology. By first focusing on a pre-defined set of known candidates from the literature, we identified potentially pathogenic variants in genes already implicated in diverse language-related syndromes, including ERC1, GRIN2A, and SRPX2. Complementary analyses suggested novel putative candidates carrying validated variants which were predicted to have functional effects, such as OXR1, SCN9A and KMT2D. We also searched for potential “multiple-hit” cases; one proband carried a rare AUTS2 variant in combination with a rare inherited haplotype affecting STARD9, while another carried a novel nonsynonymous variant in SEMA6D together with a rare stop-gain in SYNPR. On broadening scope to all rare and novel variants throughout the exomes, we identified biological themes that were enriched for such variants, including microtubule transport and cytoskeletal regulation.

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“…Experience with other complex human traits seemed to hold promise that variants in genes known through Mendelian (monogenic) disorders would also predict normal variation. Yet, genetic variation in known ID genes did not live up to this promise at present sample sizes [3,4]. Studies on parental age, a well-validated proxy variable for new mutations not shared with the parents [5], showed associations with ID and autism.…”

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confidence: 99%

“…Alternatively, if genetic interactions play the role that we ascribe to them here, we also need to consider stabilizing selection, where selective pressures have worked to make intelligence robust to genetic and environmental perturbations in either direction [21], not to increase it as much as possible. Because of that possibility, researchers should not build the assumption that very high IQ is continuous with normal intelligence into their studies by default [3,4,21]. Once enough data is in, complex models and simulations will allot roles to these mechanisms.…”

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confidence: 99%

“…In contrast, recent results suggest that in the normal range of intelligence new mutations play a minor role. However, gaps in the data remain and researchers have yet to tap into burdens of accumulated rare genetic variants in the introns (affecting gene regulation) or into non-SNP mutations (e.g., structural variation) [3]. Selective (near)-neutrality seems consistent with the existing evidence for the large fraction of heritability explained by common variants [13], since the jury is still out for the question if phenotypic links between intelligence and fitness components (fertility, longevity, sexual attractiveness, mating success) really make, or historically made, intelligence differences in the normal range visible to evolutionary selection at all.…”

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confidence: 99%

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Zeroing in on the Genetics of Intelligence

Arslan

Penke

2015

J. Intell.

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Abstract:Despite the high heritability of intelligence in the normal range, molecular genetic studies have so far yielded many null findings. However, large samples and self-imposed stringent standards have prevented false positives and gradually narrowed down where effects can still be expected. Rare variants and mutations of large effect do not appear to play a main role beyond intellectual disability. Common variants can account for about half the heritability of intelligence and show promise that collaborative efforts will identify more causal genetic variants. Gene-gene interactions may explain some of the remainder, but are only starting to be tapped. Evolutionarily, stabilizing selection and selective (near)-neutrality are consistent with the facts known so far.

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Intelligence: shared genetic basis between Mendelian disorders and a polygenic trait

Cited by 17 publications

References 45 publications

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

Zeroing in on the Genetics of Intelligence

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