Common Regulatory Variants of CYFIP1 Contribute to Susceptibility for Autism Spectrum Disorder (ASD) and Classical Autism

Based on the analysis of mRNA expression and genotype data from the “Brain Cloud” database, we identified seven SNPs within or near the autism candidate gene CYFIP1 that show nominally significant correlations between genotype and CYFIP1 mRNA expression in human dorsolateral prefrontal cortex. Analysis of transmission disequilibrium test (TDT) odds ratios (ORs) for these SNPs in a large Autism Genome Project (AGP) trio‐based association study revealed the high‐expression alleles of four of these SNPs (rs8028440, rs2289823, rs7403800 and rs3751566) to be susceptibility alleles. Correlations between the regression coefficients for mRNA expression and log10‐transformed TDT ORs were statistically significant [P = 0.008 (ASD); P = 0.002 (classical autism)]. Similarly, statistically significant correlations were obtained between levels of CYFIP1 mRNA expression predicted using the regression equations obtained from multiple linear regression analysis and log10‐transformed TDT ORs for specific combinations of genotypes for both ASD (rs2289823 + rs3751566: P = 0.008) and classical autism (rs2289823 + rs3751566: P = 0.008; rs2289823 + rs3751566 + rs765763: P = 0.0006) diagnoses. Together, these results support the hypothesis that high expression of CYFIP1 mRNA increases susceptibility for both ASD and classical autism.

[1]  Z. Hu,et al.  Common genetic variants on 1p13.2 associate with risk of autism , 2014, Molecular Psychiatry.

[2]  D. Geschwind,et al.  Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR , 2014, Molecular Psychiatry.

[3]  K. Small,et al.  ABCC5 Transporter is a Novel Type 2 Diabetes Susceptibility Gene in European and African American Populations , 2014, Annals of human genetics.

[4]  Ryan M. Smith,et al.  Family‐Based Clinical Associations and Functional Characterization of the Serotonin 2A Receptor Gene (HTR2A) in Autism Spectrum Disorder , 2014, Autism research : official journal of the International Society for Autism Research.

[5]  R. Anney,et al.  Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders , 2014, Human Genetics.

[6]  Linnaea E. Ostroff,et al.  CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation , 2013, Neuron.

[7]  Tao Li,et al.  Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population. , 2013, Schizophrenia bulletin.

[8]  Eurie L. Hong,et al.  Annotation of functional variation in personal genomes using RegulomeDB , 2012, Genome research.

[9]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[10]  J. Sutcliffe,et al.  Loci nominally associated with autism from genome-wide analysis show enrichment of brain expression quantitative trait loci but not lymphoblastoid cell line expression quantitative trait loci , 2012, Molecular Autism.

[11]  J. Leek,et al.  Temporal dynamics and genetic control of transcription in the human prefrontal cortex , 2011, Nature.

[12]  D. Stephenson,et al.  Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis , 2011, Molecular autism.

[13]  Zbyszek Otwinowski,et al.  Structure and Control of the Actin Regulatory WAVE Complex , 2010, Nature.

[14]  Margaret A. Pericak-Vance,et al.  A genome-wide scan for common alleles affecting risk for autism , 2010, Human molecular genetics.

[15]  N. Cox,et al.  Trait-Associated SNPs Are More Likely to Be eQTLs: Annotation to Enhance Discovery from GWAS , 2010, PLoS genetics.

[16]  M. Gerstein,et al.  Variation in Transcription Factor Binding Among Humans , 2010, Science.

[17]  P. Deloukas,et al.  Multiple common variants for celiac disease influencing immune gene expression , 2010, Nature Genetics.

[18]  A. Caglayan,et al.  Genetic causes of syndromic and non‐syndromic autism , 2010, Developmental medicine and child neurology.

[19]  R. Delorme,et al.  Screening for Genomic Rearrangements and Methylation Abnormalities of the 15q11-q13 Region in Autism Spectrum Disorders , 2009, Biological Psychiatry.

[20]  D. Murphy,et al.  A haplotype containing quantitative trait loci for SLC1A1 gene expression and its association with obsessive-compulsive disorder. , 2009, Archives of general psychiatry.

[21]  L. Liang,et al.  Mapping complex disease traits with global gene expression , 2009, Nature Reviews Genetics.

[22]  S. Blanton,et al.  Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. , 2009, American journal of human genetics.

[23]  Richard J. Thompson,et al.  Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre‐messenger RNA splicing , 2009, Hepatology.

[24]  K. Shianna,et al.  Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits , 2008, PLoS biology.

[25]  E. Dermitzakis,et al.  Using gene expression to investigate the genetic basis of complex disorders. , 2008, Human molecular genetics.

[26]  N. Sonenberg,et al.  The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP , 2008, Cell.

[27]  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.

[28]  B. Weir,et al.  The quantitative genetics of transcription. , 2005, Trends in genetics : TIG.

[29]  Andrew D. Johnson,et al.  Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability , 2005, Pharmacogenetics and genomics.

[30]  A. Beaudet,et al.  Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations , 2005, Journal of Medical Genetics.

[31]  L. Hurst,et al.  Evidence for selection on synonymous mutations affecting stability of mRNA secondary structure in mammals , 2005, Genome Biology.

[32]  C. Woods,et al.  Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. , 2005, American journal of human genetics.

[33]  D. Allison,et al.  Single-nucleotide polymorphisms in the C-reactive protein (CRP) gene promoter that affect transcription factor binding, alter transcriptional activity, and associate with differences in baseline serum CRP level , 2005, Journal of Molecular Medicine.

[34]  Xin Xu,et al.  Family‐based tests for associating haplotypes with general phenotype data: Application to asthma genetics , 2004, Genetic epidemiology.

[35]  Pardis C Sabeti,et al.  Linkage disequilibrium in the human genome , 2001, Nature.

[36]  M. Frotscher,et al.  Neuronal Basic Helix-Loop-Helix Proteins (NEX and BETA2/Neuro D) Regulate Terminal Granule Cell Differentiation in the Hippocampus , 2000, The Journal of Neuroscience.

[37]  T. Miyata,et al.  NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. , 1999, Genes & development.

[38]  N. Nomura,et al.  p140Sra-1 (Specifically Rac1-associated Protein) Is a Novel Specific Target for Rac1 Small GTPase* , 1998, The Journal of Biological Chemistry.

[39]  A. Battaglia,et al.  The inv dup(15) syndrome , 1997, Neurology.

[40]  S. Latt,et al.  Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. , 1989, American journal of medical genetics.

[41]  Mathieu Lemire,et al.  Common variants in the NLRP3 region contribute to Crohn's disease susceptibility , 2009, Nature Genetics.

[42]  H. Engeland,et al.  Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism , 2006, Molecular Psychiatry.

[43]  R. Doerge.  Multifactorial genetics: Mapping and analysis of quantitative trait loci in experimental populations , 2002, Nature Reviews Genetics.

[44]  J. Jankovic,et al.  The inv dup(l5) syndrome: A clinically recognizable syndrome with altered behavior, mental retardation, and epilepsy , 1997 .