Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

EMBO Molecular Medicine
Beata StepniakHannelore Ehrenreich

Abstract

Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high- versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.

References

Jan 1, 1987·Schizophrenia Bulletin·S R KayL A Opler
Jan 1, 1986·American Journal of Medical Genetics·R J HagermanM Braden
Feb 5, 1999·Journal of Autism and Developmental Disorders·D B BaileyL Mayhew
Sep 8, 2001·Genetics in Medicine : Official Journal of the American College of Medical Genetics·D C CrawfordS L Sherman
Jul 13, 2002·American Journal of Medical Genetics·Dana C CrawfordStephanie L Sherman
Sep 24, 2004·Neuropsychologia·Caroline J MooreDeclan G M Murphy
Oct 19, 2005·Schizophrenia Research·Edwin J C G Van den OordPierandrea Muglia
Dec 31, 2005·Nucleic Acids Research·Paul W C HsuIvo L Hofacker
May 16, 2006·American Journal of Medical Genetics. Part a·Deborah D HattonPenny Mirrett
Oct 13, 2006·Journal of Autism and Developmental Disorders·Sally CliffordDanuta Z Loesch
Dec 15, 2006·Lancet Neurology·Sebastien JacquemontMaureen A Leehey
May 5, 2007·Annual Review of Genomics and Human Genetics·Olga PenagarikanoStephen T Warren
Sep 26, 2007·Nature Genetics·Michael KerteszEran Segal
Jan 1, 2008·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Cary S KoganKim M Cornish
Apr 10, 2008·European Journal of Human Genetics : EJHG·Kathryn B GarberStephen T Warren
May 13, 2008·Cortex; a Journal Devoted to the Study of the Nervous System and Behavior·Kim M CornishPaul J Hagerman
Jan 9, 2009·American Journal of Mental Retardation : AJMR·Susan W HarrisRandi J Hagerman
Jun 23, 2009·Bioinformatics·Davide Rambaldi, Francesca D Ciccarelli
Oct 7, 2009·American Journal of Human Genetics·Bradford CoffeeStephen T Warren
Nov 26, 2009·Behavioural Brain Research·Regina Dahlhaus, Alaa El-Husseini
Feb 20, 2010·International Journal of Epidemiology·Henry VölzkeWolfgang Hoffmann
May 1, 2010·Human Molecular Genetics·Dolores Garcia-Arocena, Paul J Hagerman
Sep 8, 2010·Archives of General Psychiatry·Martin BegemannHannelore Ehrenreich
Nov 17, 2010·Brain Research·Bryan H King, Catherine Lord
Mar 2, 2011·The British Journal of Psychiatry : the Journal of Mental Science·Michael J OwenNicholas Craddock
May 28, 2011·Journal of Neurodevelopmental Disorders·Randi HagermanPaul Hagerman
Aug 23, 2011·Trends in Cognitive Sciences·Daniel H Geschwind
Mar 15, 2012·International Journal of Public Health·Jens KleinOlaf von dem Knesebeck
Apr 13, 2012·Autism Research : Official Journal of the International Society for Autism Research·Mayada ElsabbaghEric Fombonne

❮ Previous
Next ❯

Citations

Oct 11, 2017·Translational Psychiatry·M MitjansH Ehrenreich
May 24, 2017·Proceedings of the National Academy of Sciences of the United States of America·Sanaz Bahari-JavanAndré Fischer
Aug 29, 2018·Brain Plasticity·Natalie E PatzlaffXinyu Zhao
Feb 17, 2017·Human Molecular Genetics·Natalie E PatzlaffXinyu Zhao
Jan 19, 2019·Brain Sciences·Rachel Michelle SaréCarolyn Beebe Smith
Feb 12, 2017·Molecular Autism·Cynthia M SchumannBoryana Stamova
Feb 26, 2019·Frontiers in Synaptic Neuroscience·Claudia DanesiMaija L Castrén
Aug 9, 2018·Frontiers in Synaptic Neuroscience·Jivan Khlghatyan, Jean-Martin Beaulieu
Nov 11, 2020·European Psychiatry : the Journal of the Association of European Psychiatrists·Antonio VitaUNKNOWN Italian Network for Research on Psychoses
Nov 30, 2019·Schizophrenia Research·Giacomo DestePhilip D Harvey
Feb 12, 2021·Molecular Neurobiology·Robert EppleAndre Fischer
Oct 12, 2021·EMBO Molecular Medicine·Md Rezaul IslamAndre Fischer

❮ Previous
Next ❯

Methods Mentioned

BETA
exome sequencing
genotyping
PCR
electrophoresis

Software Mentioned

STAR
Illumina pipeline scripts
RNA
Target Scan Human
SPSS
Target Scan Human SFOLD
Typer
STATA
IMPUTE
PLINK

Related Concepts

Related Feeds

Autism

Autism spectrum disorder is associated with challenges with social skills, repetitive behaviors, and often accompanied by sensory sensitivities and medical issues. Here is the latest research on autism.

Autism: Treatment Targets

The absence of effective treatments for autism are due to the high clinical and genetic heterogeneity between affected individuals, restricted knowledge of the underlying pathophysiological mechanisms, and the lack of reliable diagnostic biomarkers. Identification of more homogenous biological subgroups is therefore essential for the development of novel treatments based on the molecular mechanisms underpinning autism and autism spectrum disorders. Find the latest research on autism treatment targets here.

Related Papers

Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine
Juthamas WirojananBeth L Goodlin-Jones
Journal of Developmental and Behavioral Pediatrics : JDBP
Beth L Goodlin-JonesR J Hagerman
Archives of Medical Research
Mónica Alejandra Rosales-ReynosoPatricio Barros-Núñez
© 2021 Meta ULC. All rights reserved