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Developmental biology - Brain Function

Estimating effects of gene mutations on IQ

Estimating impact of gene mutations on neurodevelopmental disorders and IQ...

About 3% to 7% of our population have neurodevelopmental and psychiatric disorders, including intellectual disabilities, autism spectrum disorder and schizophrenia. Genetic tests commonly performed in these patients identify 10-15% with mutations contributing to neuro-developmental disorders. However, the effect of 90% of these mutations is not known as they are very rare. So, how can the effects of these rare and unknown variants on a person's cognitive development be assessed?

A recent study published in the science journal JAMA Psychiatry, co-edited by researchers at CHU Sainte-Justine, the Université de Montréal and the Institut Pasteur in France, presents a model that can predict the effect of a genetic variant on a person's cognitive traits. This discovery opens the way to better interpretation of genetic analysis and better care for children at risk for neurodevelopmental disorders from a very young age.
"Our bodies are made up of billions of cells that each contain a nucleus. That nucleus contains genetic information recorded in DNA molecules that are made up of our 23 pairs of chromosomes, encoding more than 25,000 genes. Since we have pairs of chromosomes, we have two copies of the majority of our genes, each inherited from one parent. In this work, we studied deletions that cause genomic fragments and can lead to the loss of one or more genes. Deletions can result in an alteration of a person's cognitive development."

Guillaume Huguet PhD, co-lead author of the study.

He continues:"In practical terms, our model estimates the number of lost intellectual quotient (IQ) points induced by a deletion, wherever its location, in the patient's genome. It relies on the fact that each gene defines a piece of biological information. When a gene is modified, its biological function risks being affected. If that function is related to cognition, the patient is exposed to a risk of having a neurodevelopmental disorder. Furthermore, these effects are cumulative, leading to an increased risk."

To reach these conclusions, the research team worked on two cohort studies of the general population — a total of 2,711 people. Initially, they identified variations (deletions and duplications) in the number of copies of genes in each subjects' DNA. They then explored the intrinsic characteristics of each deletion, such as the size, number of genes lost, or the haploinsufficiency score — that organism's intolerance for losing a copy of that gene and any resulting alteration in its biological function. The team then classified their results based on their "predictive power," defining which genetic information best characterized the impact of a deletion on IQ.
To determine the relevance of their model, researchers tested it against recurring deletions with a well-known impact on IQ. The rate of agreement between the observations in the literature and the model was 75%.

According to Catherine Schramm PhD, who co-wrote the study: "We should point out that our model cannot predict the IQ of an individual, but rather the loss of IQ points associated with the presence of a deletion in his/her genome. If the mutation has a significant effect and is consistent with the cognitive impairment of the patient, we can consider that this mutation represents a major diagnostic factor in the patient."

Sébastien Jacquemont MD, a clinician-scientist at CHU Sainte-Justine and a professor in the Department of Pediatrics at the Université de Montréal: "In short, in every statistical analysis, there is a percentage of uncertainty surrounding the results. To mitigate this, you have to take into account not only predicted value, but confidence associated with that value."
The discovery proposes a new method for study of rare mutations whose rarity makes it impossible to use conventional approaches. It in fact paves the way to better clinical care for children at risk for developing a neurodevelopmental disorder.

"Our model will help clinicians estimate the cognitive impact of rare and undocumented genetic variantions. This information will allow appropriate care to be put in place to try and compensate for their impact," concludes Thomas Bourgeron PhD, professor at the Université Paris-Diderot and researcher at the Institut Pasteur, France.

The team continues to explore other behavioural characteristics that can be observed in an individual which may result from interaction of its genotype with its environment, using the same genetic analysis approach.

Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies.

To measure and estimate the effect sizes of recurrent and nonrecurrent Copy number variants (CNVs) on IQ.

This study identified all Copy number variants (CNVs) that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data.

Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo Copy number variant (CNV) events.

The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points (P = 6 × 10-4); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant (P = 8 × 10-5). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10-88). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database.

Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic.

Authors: Huguet G, Schramm C, Douard E, Jiang L, Labbe A, Tihy F, Mathonnet G, Nizard S, Lemyre E, Mathieu A, Poline J B, Loth E, Toro R, Schumann G, Conrod P, Pausova Z, Greenwood C, Paus T, Bourgeron T, Jacquemont S; IMAGEN Consortium.

About the study
The article titled "Measuring and predicting the effect of copy number variants on general intelligence in community-based samples" was published in the journal JAMA Psychiatry in March 2018. The co-lead authors are Guillaume Huguet, PhD, and Catherine Schramm, PhD, both postdoctoral fellows under the direction of Sébastien Jacquemont at the CHU Sainte-Justine. The co-principal authors are Sébastien Jacquemont, MD, a doctor, geneticist and researcher at the CHU Sainte-Justine, associate professor in the Department of Pediatrics at the Université de Montréal and the scientific director of CARTaGENE, and Thomas Bourgeron, PhD, researcher at the Institut Pasteur, France, and assistant professor at the Université Paris-Diderot.

This research was enabled by support provided by Calcul Quebec and Compute. Dr Bourgeron is supported by the Institut Pasteur, the University Paris Diderot, and the Bettencourt-Schueller Foundation. Dr Jacquemont is a recipient of a Bursary Professor fellowship of the Swiss National Science Foundation, a Canada Research Chair in neurodevelopmental disorders, and a chair from the Jeanne et Jean Louis Levesque Foundation. Dr Huguet is supported by the Sainte-Justine Foundation, the Merit scholarship program for foreign students, and the Network of Applied Genetic Medicine fellowships. Dr Schramm is supported by the Institute for Data Valorization fellowship. Dr Loth is supported by European Autism Interventions, which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement 115300, the resources of which are composed of financial contributions from grant FP7/2007-2013 from the European Union's Seventh Framework Programme, the European Federation of Pharmaceutical Industries and Associations companies' in-kind contributions, and Autism Speaks. This work is supported by a grant from the Brain Canada Multi Investigator initiative (Dr Jacquemont). The Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada fund the Saguenay Youth Study. Funding for the project was provided by the Wellcome Trust.

About the CHU Sainte-Justine Research Center
The CHU Sainte-Justine Research Center is a leading mother-child research institution affiliated with Université de Montréal. It brings together more than 200 research investigators, including over 90 clinician-scientists, as well as 450 graduate and postgraduate students focused on finding innovative prevention means, faster and less invasive treatments, as well as personalized approaches to medicine. The Center is part of the CHU Sainte-Justine, which is the largest mother-child center in Canada and second pediatric center in North America. More at research.chusj.org

About the Institut Pasteur
The Institut Pasteur, a public interest organization set up by Louis Pasteur in 1887 and inaugurated on November 14, 1888, has been an internationally renowned biomedical research center for 130 years, with a network of 33 institutes on five continents. In the pursuit of its mission to prevent and fight against diseases in France and throughout the world, the Institut Pasteur operates in four main areas: scientific and medical research, public health and health monitoring, teaching, and business development and technology transfer. More than 2,500 people work on its Paris campus. The Institut Pasteur is a globally recognized leader in infectious diseases, microbiology, and immunology. It also focuses its research on certain cancers, genetic and neurodegenerative diseases, genomics and developmental biology. This research aims to expand our knowledge of living organisms in a bid to lay the foundation for new prevention strategies and novel therapeutics. Since its inception, ten Institut Pasteur scientists have been awarded the Nobel Prize for Medicine, including two in 2008 for the 1983 discovery of the human immunodeficiency virus (HIV) that causes AIDS.

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The Institut Pasteur focuses its research on certain cancers, genetic and neurodegenerative diseases, genomics and developmental biology. Image: New Zealand Brain Research Institute.

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