Towards a gene-level map of resilience to genetic variants associated with autism

While over 100 genes are now significantly associated with autism spectrum disorders (ASD), the penetrance of the variants affecting these genes remains poorly understood. Here, we quantified the prevalence of rare loss-of-function (LoF) mutations affecting 156 genes robustly associated with ASD (SPARK genes) using genetic data from more than 10,000 individuals with ASD and 100,000 undiagnosed individuals. We then investigated the clinical, brain imaging and genetic profiles of individuals heterozygous for these rare deleterious variants who were not diagnosed with ASD. These "resilient" individuals, observed in less than 1% of the general population, were equally distributed among males and females, but displayed low polygenic scores for ASD compared to LoF heterozygotes diagnosed with ASD. The interplay between rare and common variants may therefore contribute to the clinical profiles of the individuals carrying LoF in genes associated with ASD.

[1]  S. Scherer,et al.  Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome , 2020, Nature Medicine.

[2]  Patrick J. Short,et al.  Evidence for 28 genetic disorders discovered by combining healthcare and research data , 2020, Nature.

[3]  Jonathan M. Mudge,et al.  Transcript expression-aware annotation improves rare variant interpretation , 2020, Nature.

[4]  W. Chung,et al.  A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants. , 2020, The American journal of psychiatry.

[5]  Brent S. Pedersen,et al.  Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches , 2019, Genome Medicine.

[6]  B. O’Roak,et al.  Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes , 2019, npj Genomic Medicine.

[7]  Alicia R. Martin,et al.  Identification of common genetic risk variants for autism spectrum disorder , 2019, Nature Genetics.

[8]  G. Kirov,et al.  Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank , 2019, The British Journal of Psychiatry.

[9]  Ryan L. Collins,et al.  The mutational constraint spectrum quantified from variation in 141,456 humans , 2020, Nature.

[10]  Trygve E Bakken,et al.  Neurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity , 2018, Nature Genetics.

[11]  Andrew H. Chiang,et al.  Exons as units of phenotypic impact for truncating mutations in autism , 2018, bioRxiv.

[12]  Stephane E. Castel,et al.  Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk , 2018, Nature Genetics.

[13]  T. Bourgeron,et al.  Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples , 2018, JAMA psychiatry.

[14]  P. Szatmari.  Risk and resilience in autism spectrum disorder: a missed translational opportunity? , 2018, Developmental medicine and child neurology.

[15]  Anibal Gutierrez,et al.  SPARK: A US Cohort of 50,000 Families to Accelerate Autism Research , 2018, Neuron.

[16]  Jakob Grove,et al.  Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders , 2016, Nature Genetics.

[17]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

[18]  Brian T. Naughton,et al.  Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases , 2016, Nature Biotechnology.

[19]  F. Cunningham,et al.  The Ensembl Variant Effect Predictor , 2016, bioRxiv.

[20]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[21]  Christopher S. Poultney,et al.  Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci , 2015, Neuron.

[22]  T. Bourgeron.  From the genetic architecture to synaptic plasticity in autism spectrum disorder , 2015, Nature Reviews Neuroscience.

[23]  Somer Bishop,et al.  Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority , 2015, Molecular Autism.

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

[25]  J. Sebat,et al.  Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases , 2015, Neuron.

[26]  Jack Euesden,et al.  PRSice: Polygenic Risk Score software , 2014, Bioinform..

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

[28]  D. Geschwind,et al.  Sex differences in autism spectrum disorders. , 2013, Current opinion in neurology.

[29]  D. Pinto,et al.  SHANK1 Deletions in Males with Autism Spectrum Disorder. , 2012, American journal of human genetics.

[30]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration , 2012, Briefings Bioinform..

[31]  Joel N Hirschhorn,et al.  Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation , 2010, Nature Genetics.

[32]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[33]  David H. Alexander,et al.  Fast model-based estimation of ancestry in unrelated individuals. , 2009, Genome research.

[34]  P. Visscher,et al.  Common polygenic variation contributes to risk of schizophrenia and bipolar disorder , 2009, Nature.

[35]  E. Birney,et al.  Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt , 2009, Nature Protocols.

[36]  Andrew Menzies,et al.  X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment , 2008, Nature Genetics.

[37]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[38]  C Eng,et al.  Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations , 2005, Journal of Medical Genetics.

[39]  Alexander Pertsemlidis,et al.  Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 , 2005, Nature Genetics.

[40]  Toshihiro Tanaka.  The International HapMap Project , 2003, Nature.

[41]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.