A framework for the investigation of rare genetic disorders in neuropsychiatry

Sanders, Stephan; Şahin, Mustafa; Hostyk, Joseph; Thurm, Audrey; Jacquemont, Sébastien; Avillach, Paul; Douard, Élise; Martin, Christa Lese; Modi, Meera E.; Moreno-De-Luca, Andrés; Raznahan, Armin; Antičević, Alan; Dolmetsch, Ricardo; Feng, Guoping; Geschwind, Daniel H.; Glahn, David C.; Goldstein, David B.; Ledbetter, David H.; Mullé, Jennifer G.; Paşca, Sergiu P.; Samaco, Rodney C.; Sebat, Jonathan; Pariser, Anne; Lehner, Thomas; Gur, Raquel E.; Bearden, Carrie E.

doi:10.1038/s41591-019-0581-5

Cited by 106 publications

(89 citation statements)

References 136 publications

(178 reference statements)

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“…We compared the autism risk estimated by our model to that previously published for recurrent CNVs. Our literature search identified 16 CNVs with available odds ratios (ORs) (9,12,13,40) (Table S6 in the online supplement). The model was trained using a pooled dataset including SSC and MSSNG probands, unaffected siblings, and unselected populations, excluding these 16 CNVs.…”

Section: Estimating and Validating The Level Of Autism Riskmentioning

confidence: 99%

“…(2) (4,9,22) (Table S3 in the online supplement). OR estimates from the model overlap with the 95% confidence interval (CI) of ORs from previous publications for 14 recurrent CNVs.…”

Section: Mssng Sscmentioning

confidence: 99%

“…(6)(7)(8) The largest rare variant autism case-control association studies to date have formally associated 91 genes and CNVs at only 13 genomic loci. (9)(10)(11)(12)(13) Many more genomic loci are likely implicated as suggested by the overall increase in CNV burden associated with autism. (9,12,(14)(15)(16) Therefore, the susceptibility to autism conferred by most CNVs remains undocumented.…”

Section: Introductionmentioning

confidence: 99%

“…(9)(10)(11)(12)(13) Many more genomic loci are likely implicated as suggested by the overall increase in CNV burden associated with autism. (9,12,(14)(15)(16) Therefore, the susceptibility to autism conferred by most CNVs remains undocumented. This is particularly problematic in the neurodevelopmental clinic, where undocumented CNVs are routinely diagnosed in a large proportion of patients.…”

Section: Introductionmentioning

confidence: 99%

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Effects-sizes of deletions and duplications on autism risk across the genome

Douard

Zeribi

Schramm

et al. 2020

Preprint

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Objective: Deleterious copy number variants (CNVs) are identified in up to 20% of individuals with autism. However, only 13 genomic loci have been formally associated with autism because the majority of CNVs are too rare to perform individual association studies. To investigate the implication of undocumented CNVs in neurodevelopmental disorders, we recently developed a new framework to estimate their effect-size on intelligence quotient (IQ) and sought to extend this approach to autism susceptibility and multiple cognitive domains. Methods: We identified CNVs in two autism samples (Simons Simplex Collection and MSSNG) and two unselected populations (IMAGEN and Saguenay Youth Study). Statistical models integrating scores of genes encompassed in CNVs were used to explain their effect on autism susceptibility and multiple cognitive domains. Results: Among 9 scores of genes, the "probability-of-being loss-of-function intolerant" (pLI) best explains the effect of CNVs on IQ and autism risk. Deletions decrease IQ by a mean of 2.6 points per point of pLI. The effect of duplications on IQ is three-fold smaller.The odd ratios for autism increases when deleting or duplicating any point of pLI. This increased autism risk is similar in subgroups of individuals below or above median IQ.Once CNV effects on IQ are accounted for, autism susceptibility remains mostly unchanged for duplications but decreases for deletions. Model estimates for autism risk overlap with previously published observations. Deletions and duplications differentially affect social communication, behaviour, and phonological memory, whereas both equally affect motor skills.Conclusions: Autism risk conferred by duplications is less influenced by IQ compared to deletions. CNVs increase autism risk similarly in individuals with high and low IQ. Our model, trained on CNVs encompassing >4,500 genes, suggests highly polygenic properties of gene dosage with respect to autism risk. These models will help interpreting CNVs identified in the clinic.

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Section: Estimating and Validating The Level Of Autism Riskmentioning

confidence: 99%

“…(2) (4,9,22) (Table S3 in the online supplement). OR estimates from the model overlap with the 95% confidence interval (CI) of ORs from previous publications for 14 recurrent CNVs.…”

Section: Mssng Sscmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects-sizes of deletions and duplications on autism risk across the genome

Douard

Zeribi

Schramm

et al. 2020

Preprint

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“…This suggests that the risk conferred by genetic variants and the associated FC-patterns represent important dimensions that are necessary but insufficient to cause disease. Additional factors and associated FC-patterns are required (incomplete penetrance39 ). Bottom-up approaches studying rare variants have almost exclusively been performed individually.…”

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confidence: 99%

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Moreau

Urchs

Orban

et al. 2019

Preprint

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16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) networks remains unclear.We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify major dimensions contributing to complex idiopathic conditions. CNVs had large mirror effects on FC at the global and regional level, and their effect-sizes were twice as large as those of idiopathic conditions. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD.Individuals with higher similarity to deletion FC-signatures exhibited worse behavioral and cognitive symptoms. These seemingly distinct neuropsychiatric mutations showed similar gene co-expression patterns and converged on FC dimensions, that may represent mechanistic building blocks shared across idiopathic conditions.

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Functional Characterization of MC4R Variants in Chinese Morbid Obese Patients and Weight Loss after Bariatric Surgery

Gong

Huang

et al. 2023

Advanced Biology

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Mutations in MC4R are the most common genetic cause of obesity. In the reported Chinese morbid obesity cohort, 10 out of 59 harbor six MC4R variants, including Y35C, T53I, V103I, R165W, G233S, and C277X, among which V103I has a relatively high frequency, while other five variants are rare in the population. The prevalence of MC4R carriers in Chinese morbid obese patients (body mass index ≥ 45 kg m−2) is detected as 16.9% in this study. R165W and C277X are loss‐of‐function variants. The patient with R165W achieves excess weight loss (%EWL) as high as 20.6% and 50.3% at 1 and 8 months after surgery, respectively. G233S is reported for the first time in Asia obese population. The patient harboring G233S has a %EWL as 23.3% one month postsurgery. It is concluded that morbid obese patients with rare MC4R variants can benefit from metabolic surgery. More importantly, the choice of surgery procedure and MC4R variant should be taken into consideration for personalized treatment. In the future, a larger size cohort, accompanied with regular and longer follow‐up, would be helpful.

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A framework for the investigation of rare genetic disorders in neuropsychiatry

Cited by 106 publications

References 136 publications

Effects-sizes of deletions and duplications on autism risk across the genome

Effects-sizes of deletions and duplications on autism risk across the genome

Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia

Functional Characterization of MC4R Variants in Chinese Morbid Obese Patients and Weight Loss after Bariatric Surgery

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