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A High-Density SNP Genome-Wide Linkage Scan in a Large Autism

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A High-Density SNP Genome-Wide Linkage Scan in a Large Autism Molecular Psychiatry (2009) 14, 590–600 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp ORIGINAL ARTICLE A high-density SNP genome-wide linkage scan in a large autism extended pedigree K Allen-Brady1, J Miller1, N Matsunami2, J Stevens1, H Block1, M Farley1, L Krasny1, C Pingree1, J Lainhart1, M Leppert1, WM McMahon1 and H Coon1 1Department of Psychiatry, University of Utah, Salt Lake City, UT, USA and 2Department of Human Genetics, University of Utah, Salt Lake City, UT, USA We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2–q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31–q27.3 (NPL, 4.85) and 20q11.21–q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1–p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow- up of these chromosomal regions is warranted. Molecular Psychiatry (2009) 14, 590–600; doi:10.1038/mp.2008.14; published online 19 February 2008 Keywords: autism spectrum disorder; genome-wide scan; chromosome 3; chromosome 20; chromosome 7; chromosome 9 Introduction of such genomic searches have been published to date.5–17 However, no single chromosomal region has Autism (MIM 209850) is a pervasive neurodevelop- been consistently shown to be associated with autism. mental disorder, characterized by impairments in Numerous reasons for the lack of consistency of verbal and nonverbal communication and social results exist including genetic heterogeneity, such interaction, and the presence of repetitive stereotyped that multiple genes are thought to be involved in the behaviors and interests. Autism is a member of a etiology of autism.9,18 It has been suggested that as few spectrum of neurodevelopmental disorders (autism as 3–4 genes19 and perhaps up to 15 predisposing spectrum disorders (ASDs)), which also includes genes9 may be involved, and the complexity of Asperger’s syndrome, and pervasive developmental finding multiple genes is further increased as autism disorder, not otherwise specified (PDD-NOS). It is predisposition genes do not appear to be inherited in typically diagnosed within the first 3 years of life, and a simple Mendelian fashion. Furthermore, genetic there is strong evidence that autism is highly and environmental interactions may also contribute heritable. The concordance rate in monozygotic twins to the autism phenotype.20,21 In addition, the inclusion is 70–90%,1,2 and the autism rate in siblings is 3–5%, of heterogeneous phenotypes may explain the lack of much higher than expected from the general popula- consistency of results in the study of autism. Genome- tion prevalence.3,4 Despite the strong heritability, wide linkage scans that stratify subjects into more identification of the underlying genetic mechanisms homogeneous phenotypes have shown striking differ- for autism has been elusive. ences in linkage results, including differences by the Efforts to find autism predisposition genes have strictness of the definition of autism,16,22 sex,16,23 focused on genome-wide linkage scans, and a number developmental regression,16,24 language delay25,26 and repetitive behaviors.27,28 The key to identification of Correspondence: Dr K Allen-Brady, Utah Autism Research autism susceptibility genes will be the reduction of both Program, 650 Komas Drive, Suite 206, Salt Lake City, UT 84108, genetic and phenotypic heterogeneity through selection USA. E-mail: [email protected] of well-characterized families. Received 30 November 2006; revised 21 December 2007; accepted While most linkage studies to date have utilized 2 January 2008; published online 19 February 2008 nuclear families composed of either trios (two parents High-density linkage in large autism pedigree K Allen-Brady et al 591 and an affected offspring), or sibling pairs (concor- Materials and methods dant or discordant), large extended pedigrees offer many advantages for the localization of candidate Subjects genes for autism. The study of large extended The seven affected male subjects are all descendants pedigrees increases the likelihood that there will be of a single founding couple of Northern European greater phenotype homogeneity and reduced environ- ancestry (see Figure 1). To preserve confidentiality of mental heterogeneity by pedigree. Study of large the pedigree, most siblings are excluded. Diagnosis pedigrees also increases the power of a study to was based on Diagnostic and Statistical Manual of detect disease predisposition genes because of re- Mental Disorders, fourth edition, Text Revision duced genetic heterogeneity by pedigree. While study (DSM-IV-TR) criteria. Developmental history and of large autism pedigrees affords many advantages, clinical observations were gathered using the Autism because of the relatively low autism recurrence risk in Diagnostic Interview-Revised (ADI-R) and the relatives, finding large extended autism pedigrees is a Autism Diagnostic Observation Schedule-Generic challenge. (ADOS-G),30,31 respectively, with two exceptions. Here, we present results for a high-density One subject was unavailable for ADOS-G testing, single nucleotide polymorphism (SNP) genome- and another subject’s ADI-R was considered unreli- wide linkage analysis in a six-generation pedigree able, as the informant was elderly and unable to recall from Utah with seven affected males, which is one subtle aspects of early development. However, in both of the largest known autism pedigrees. Previously, cases there was also documentation of an earlier we published linkage results using this same pedigree diagnosis and/or very early concerns about social for a single chromosomal region (3q25–27).29 In development such that, along with current informa- our current study, we present results for a genome- tion gathered through our testing, DSM-IV-TR criteria wide two-stage linkage design. In stage 1, an for autistic disorder was met. Six of the seven affected initial linkage screen was performed to identify subjects met DSM-IV-TR criteria for autistic disorder. potential regions of interest. We confirmed potentially One subject (subject no. 5) met DSM-IV-TR criteria for interesting regions in stage 2 by eliminating SNPs PDD-NOS. As one of the seven affected subjects was in high LD. Maximizing genetic and phenotypic diagnosed with PDD-NOS, we define the entire homogeneity through study of a highly informa- pedigree as an ASD pedigree. tive pedigree using an increased genetic-marker Other clinical characteristics of the seven affected density increases the probability of both confirming subjects have been assessed; however, little similarity and narrowing significant linkage regions between cases was observed. Full-scale intelligence previously published for autism, as well as further quotient (IQ) scores of affected subjects ranged from facilitating the identification of autism predisposition 41 to 124 for verbal IQ (VIQ) and 45 to 140 for genes. performance IQ (PIQ) using IQ measures appropriate **** * * * * * * * * * * 6 * * * * 1 3 * 4 * * 2 * 7 5 Figure 1 Basic pedigree structure of extended autism pedigree. Affected subjects are shaded and numbered; deceased subjects are indicated with a slash. All unaffected persons shown in this figure with an asterisk (*) were genotyped as were all affected subjects (7 affected subjects and 22 relatives). Molecular Psychiatry High-density linkage in large autism pedigree K Allen-Brady et al 592 for age and level of functioning (Wechsler Adult SNP genotyping Intelligence Scale (WAIS-III),32 Wechsler Intelligence We genotyped the 7 affected individuals and the 22 Scale for Children (WISC-III)33 or Differential Abili- unaffected relatives using the Affymetrix 10K SNP ties Scale (DAS)34). Three of the seven affected panel. The 10K SNP panel contains 10 660 SNPs on a subjects showed language delay (that is, onset of single array, and has an average distance between single words after 24 months and/or onset of phrases SNPs of 210 kb. SNP genotypes were obtained by after 33 months) as measured by items on the ADI-R. following the Affymetrix protocol for the GeneChip One of the affected subjects had a history of Mapping 10K Xba Array.37 In brief, 250 ng of genomic nonfebrile seizures, but the other six did not. None DNA taken from peripheral blood was digested with of the seven subjects showed developmental regres- the Xba1 restriction enzyme into fragments. This step sion (that is, loss of previously gained language and is followed by ligation to Xba adaptors that place no social skills) as measured by items on the ADI-R. See restriction on fragment size. Using PCR reaction, a Table 1 for details of these phenotypes. single generic primer is used to amplify adaptor- We included 22 unaffected living relatives from the ligated DNA fragments. The amplified DNA product same pedigree to infer genotypes of deceased relatives is then fragmented, labeled with biotin-ddATP and or phase for genotyped cases. Phenotypes for the hybridized to the 10K chip. Following an 18-hour unaffected relatives were set to ‘unknown’ or missing hybridization, the chip is washed, stained and for all analyses, as phenotype status of the deceased scanned using an Affymetrix Fluidics Station FS450 relatives was not recorded or possible to determine.
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