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A framework for the investigation of rare genetic disorders in neuropsychiatry.

ABSTRACT: De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies.

SUBMITTER: Sanders SJ

PROVIDER: S-EPMC8656349 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A framework for the investigation of rare genetic disorders in neuropsychiatry.

Sanders Stephan J SJ Sahin Mustafa M Hostyk Joseph J Thurm Audrey A Jacquemont Sebastien S Avillach Paul P Douard Elise E Martin Christa L CL Modi Meera E ME Moreno-De-Luca Andres A Raznahan Armin A Anticevic Alan A Dolmetsch Ricardo R Feng Guoping G Geschwind Daniel H DH Glahn David C DC Goldstein David B DB Ledbetter David H DH Mulle Jennifer G JG Pasca Sergiu P SP Samaco Rodney R Sebat Jonathan J Pariser Anne A Lehner Thomas T Gur Raquel E RE Bearden Carrie E CE

Nature medicine 20190923 10

De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We thin ...[more]

PMID: 31548702

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Project description:BackgroundLanguage plays a major role in human behavior. For this reason, neurodevelopmental and psychiatric disorders in which linguistic ability is impaired could have a big impact on the individual's social interaction and general wellbeing. Such disorders tend to have a strong genetic component, but most past studies examined mostly the linguistic overlaps across these disorders; investigations into their genetic overlaps are limited. The aim of this study was to assess the potential genetic overlap between language impairment and broader behavioral disorders employing methods capturing both common and rare genetic variants.MethodsWe employ polygenic risk scores (PRS) trained on specific language impairment (SLI) to evaluate genetic overlap across several disorders in a large case-cohort sample comprising ~13,000 autism spectrum disorder (ASD) cases, including cases of childhood autism and Asperger's syndrome, ~15,000 attention deficit/hyperactivity disorder (ADHD) cases, ~3000 schizophrenia cases, and ~21,000 population controls. We also examine rare variants in SLI/language-related genes in a subset of the sample that was exome-sequenced using the SKAT-O method.ResultsWe find that there is little evidence for genetic overlap between SLI and ADHD, schizophrenia, and ASD, the latter being in line with results of linguistic analyses in past studies. However, we observe a small, significant genetic overlap between SLI and childhood autism specifically, which we do not observe for SLI and Asperger's syndrome. Moreover, we observe that childhood autism cases have significantly higher SLI-trained PRS compared to Asperger's syndrome cases; these results correspond well to the linguistic profiles of both disorders. Our rare variant analyses provide suggestive evidence of association for specific genes with ASD, childhood autism, and schizophrenia.ConclusionsOur study provides, for the first time, to our knowledge, genetic evidence for ASD subtypes based on risk variants for language impairment.

Project description:There have been two major eras in the history of gene discovery. The first was the era of linkage analysis, with approximately 1,300 disease-related genes identified by positional cloning by the turn of the millennium. The second era has been powered by two major breakthroughs: the publication of the human genome and the development of massively parallel sequencing (MPS). MPS has greatly accelerated disease gene identification, such that disease genes that would have taken years to map previously can now be determined in a matter of weeks. Additionally, the number of affected families needed to map a causative gene and the size of such families have fallen: de novo mutations, previously intractable by linkage analysis, can be identified through sequencing of the parent-child trio, and genes for recessive disease can be identified through MPS even of a single affected individual. MPS technologies include whole exome sequencing (WES), whole genome sequencing (WGS), and panel sequencing, each with their strengths. While WES has been responsible for most gene discoveries through MPS, WGS is superior in detecting copy number variants, chromosomal rearrangements, and repeat-rich regions. Panels are commonly used for diagnostic purposes as they are extremely cost-effective and generate manageable quantities of data, with no risk of unexpected findings. However, in instances of diagnostic uncertainty, it can be challenging to choose the right panel, and in these circumstances WES has a higher diagnostic yield. MPS has ethical, social, and legal implications, many of which are common to genetic testing generally but amplified due to the magnitude of data (e.g., relationship misattribution, identification of variants of uncertain significance, and genetic discrimination); others are unique to WES and WGS technologies (e.g., incidental or secondary findings). Nonetheless, MPS is rapidly translating into clinical practice as an extremely useful part of the clinical armamentarium.

Dataset Information

A framework for the investigation of rare genetic disorders in neuropsychiatry.

Publications

A framework for the investigation of rare genetic disorders in neuropsychiatry.

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