Autism spectrum disorder severity reflects the average contribution of de novo and familial influences

Significance Autism spectrum disorder (ASD) research is complicated by heterogeneity. There are several types of genetic risk factors for ASDs, and that diversity may be reflected in case presentation. This study presents evidence for systematic variation in the genetic architecture of ASDs in which higher functioning cases, defined through cognitive and behavioral assessments, are more likely to manifest familial influences. This finding suggests that genetic and neurobiological research into ASDs and other neuropsychiatric disorders may be pursued more efficiently through greater phenotypic characterization. Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions—phenotypically and genetically—although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

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

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

[3]  Sven Bergmann,et al.  A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. , 2014, American journal of human genetics.

[4]  P. Visscher,et al.  Childhood intelligence is heritable, highly polygenic and associated with FNBP1L , 2014, Molecular Psychiatry.

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

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

[7]  R Plomin,et al.  DNA evidence for strong genetic stability and increasing heritability of intelligence from age 7 to 12 , 2013, Molecular Psychiatry.

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

[9]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

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

[11]  R. Reading,et al.  Diagnostic exome sequencing in persons with severe intellectual disability , 2013 .

[12]  Angelica Ronald,et al.  Examining and interpreting the female protective effect against autistic behavior , 2013, Proceedings of the National Academy of Sciences.

[13]  Letitia R. Naigles,et al.  Optimal outcome in individuals with a history of autism , 2013, BDJ.

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

[15]  D. Horn,et al.  Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study , 2012, The Lancet.

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

[17]  Andrew Pickles,et al.  Trajectories of Autism Severity in Children Using Standardized ADOS Scores , 2012, Pediatrics.

[18]  R. Vasa,et al.  Mood Disorders in Mothers of Children on the Autism Spectrum Are Associated with Higher Functioning Autism , 2012, Autism research and treatment.

[19]  D. Geschwind,et al.  Autism genetics: searching for specificity and convergence , 2012, Genome Biology.

[20]  Margaret A. Pericak-Vance,et al.  Individual common variants exert weak effects on the risk for autism spectrum disorders , 2012, Human molecular genetics.

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

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

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

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

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

[26]  Ian J. Deary,et al.  Genetic contributions to stability and change in intelligence from childhood to old age , 2012, Nature.

[27]  C. Gillberg,et al.  Autism spectrum disorders and autistic like traits: similar etiology in the extreme end and the normal variation. , 2012, Archives of general psychiatry.

[28]  F. Happé,et al.  Evidence that autistic traits show the same etiology in the general population and at the quantitative extremes (5%, 2.5%, and 1%). , 2011, Archives of general psychiatry.

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

[30]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[31]  Lorna M. Lopez,et al.  Genome-wide association studies establish that human intelligence is highly heritable and polygenic , 2011, Molecular Psychiatry.

[32]  Boris Yamrom,et al.  Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders , 2011, Neuron.

[33]  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.

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

[35]  C. Lord,et al.  The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors , 2010, Neuron.

[36]  S. Baron-Cohen,et al.  Defining the broader, medium and narrow autism phenotype among parents using the Autism Spectrum Quotient (AQ) , 2010, Molecular autism.

[37]  D. Skuse.  Is autism really a coherent syndrome in boys, or girls? , 2009, British journal of psychology.

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

[39]  C. King,et al.  Prevalence of depression by race/ethnicity: findings from the National Health and Nutrition Examination Survey III. , 2005, American journal of public health.

[40]  D. Finkelhor,et al.  ADMINISTRATION AND SCORING MANUAL , 2001 .

[41]  S. Bradley-Johnson.  Mullen Scales of Early Learning , 1997 .

[42]  P. L. Nichols.  Familial mental retardation , 1984, Behavior genetics.