Genetic research in autism spectrum disorders

Purpose of review The recent explosion of genetic findings in autism spectrum disorder (ASD) research has improved knowledge of the disorder's underlying biology and etiologic architecture. This review introduces concepts and results from recent genetic studies and discusses the manner in which those findings can influence the trajectory of ASD research. Recent findings Large consortium studies have associated ASDs with many types of genetic risk factors, including common polygenic risk, de novo single nucleotide variants, copy number variants, and rare inherited variants. In aggregate, these results confirm the heterogeneity and complexity of ASDs. The rare variant findings in particular point to genes and pathways that begin to bridge the gap between behavior and biology. Summary Genetic studies have the potential to identify the biological underpinnings of ASDs and other neuropsychiatric disorders. The data they generate are already being used to examine disease pathways and pathogenesis. The results also speak to ASD heterogeneity and, in the future, may be used to stratify research studies and treatment trials.

[1]  N. Risch,et al.  Familial recurrence of autism spectrum disorder: evaluating genetic and environmental contributions. , 2014, The American journal of psychiatry.

[2]  Tomas W. Fitzgerald,et al.  Large-scale discovery of novel genetic causes of developmental disorders , 2014, Nature.

[3]  M. Daly,et al.  Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis , 2013, The Lancet.

[4]  Kali T. Witherspoon,et al.  Excess of rare, inherited truncating mutations in autism , 2015, Nature Genetics.

[5]  Yi Zhang,et al.  Sibling recurrence and the genetic epidemiology of autism. , 2010, The American journal of psychiatry.

[6]  David W. Evans,et al.  The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions. , 2015, JAMA psychiatry.

[7]  Kenny Q. Ye,et al.  De Novo Gene Disruptions in Children on the Autistic Spectrum , 2012, Neuron.

[8]  J. Sebat,et al.  Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. , 2009, Trends in genetics : TIG.

[9]  Kathryn Roeder,et al.  Rare Complete Knockouts in Humans: Population Distribution and Significant Role in Autism Spectrum Disorders , 2013, Neuron.

[10]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[11]  M. Daly,et al.  An Atlas of Genetic Correlations across Human Diseases and Traits , 2015, Nature Genetics.

[12]  Bradley P. Coe,et al.  Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations , 2012, Nature.

[13]  S. Bryson,et al.  Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study , 2011, Pediatrics.

[14]  D. Geschwind,et al.  Rare Inherited Variation in Autism: Beginning to See the Forest and a Few Trees , 2013, Neuron.

[15]  Jessica R. Wolff,et al.  Microduplications of 16p11.2 are Associated with Schizophrenia , 2009, Nature Genetics.

[16]  Patrick F. Sullivan,et al.  Genetic architectures of psychiatric disorders: the emerging picture and its implications , 2012, Nature Reviews Genetics.

[17]  Evan T. Geller,et al.  Patterns and rates of exonic de novo mutations in autism spectrum disorders , 2012, Nature.

[18]  Angelica Ronald,et al.  Autism spectrum disorders and autistic traits: A decade of new twin studies , 2011, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[19]  Kathryn Roeder,et al.  Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism , 2011, Neuron.

[20]  E. Banks,et al.  De novo mutations in schizophrenia implicate synaptic networks , 2014, Nature.

[21]  Kathryn Roeder,et al.  Most genetic risk for autism resides with common variation , 2014, Nature Genetics.

[22]  Stephan J Sanders,et al.  A framework for the interpretation of de novo mutation in human disease , 2014, Nature Genetics.

[23]  M. Daly,et al.  Autism spectrum disorder severity reflects the average contribution of de novo and familial influences , 2014, Proceedings of the National Academy of Sciences.

[24]  J. Baio,et al.  Prevalence of Autism Spectrum Disorders: Autism and Developmental Disabilities Monitoring Network, United States, 2006. Morbidity and Mortality Weekly Report. Surveillance Summaries. Volume 58, Number SS-10. , 2009 .

[25]  C. Spencer,et al.  A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium , 2016, bioRxiv.

[26]  Boris Yamrom,et al.  The contribution of de novo coding mutations to autism spectrum disorder , 2014, Nature.

[27]  P. Sullivan,et al.  Family history of schizophrenia and bipolar disorder as risk factors for autism. , 2012, Archives of general psychiatry.

[28]  Raphael Bernier,et al.  The Cognitive and Behavioral Phenotype of the 16p11.2 Deletion in a Clinically Ascertained Population , 2015, Biological Psychiatry.

[29]  P. Bearman,et al.  Diagnostic change and the increased prevalence of autism. , 2009, International journal of epidemiology.

[30]  M. Daly,et al.  LD Score regression distinguishes confounding from polygenicity in genome-wide association studies , 2014, Nature Genetics.

[31]  Jay Shendure,et al.  Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development , 2014, Cell.

[32]  Eric S. Lander,et al.  A polygenic burden of rare disruptive mutations in schizophrenia , 2014, Nature.

[33]  Michael Wigler,et al.  The role of de novo mutations in the genetics of autism spectrum disorders , 2014, Nature Reviews Genetics.

[34]  Jianxin Shi,et al.  Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs , 2013, Nature Genetics.

[35]  D. Geschwind,et al.  Autism recurrence in half siblings: strong support for genetic mechanisms of transmission in ASD , 2013, Molecular Psychiatry.

[36]  Michael F. Walker,et al.  De novo mutations revealed by whole-exome sequencing are strongly associated with autism , 2012, Nature.

[37]  Eric Fombonne,et al.  Epidemiology of autistic disorder and other pervasive developmental disorders. , 2005, The Journal of clinical psychiatry.

[38]  Eric M. Morrow,et al.  A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity? , 2015, Biological Psychiatry.

[39]  Christopher S. Poultney,et al.  Synaptic, transcriptional, and chromatin genes disrupted in autism , 2014, Nature.

[40]  C. Spencer,et al.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci , 2014, Nature.

[41]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.