A high-density SNP genome-wide linkage scan in a large autism extended pedigree

Abstract

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 followup of these chromosomal regions is warranted.

Genome-wide linkage in Utah autism pedigrees

“…7 The current sample includes this original pedigree, but these regions were not strongly supported by the new pedigrees. Within these 70 pedigrees, our strongest signals in any of these previous regions were on chromosomes 9p24.3 (HLOD=1.30 at 2,202,546 bp) and 20q11.21-q13.12 (HLOD=1.23 at 40,018,916 bp), but both of these regions were below the suggestive linkage threshold.…”

“…7 In this previous study, we identified three chromosomal regions meeting genome-wide linkage significance criteria at 3q13.2-13.31, 3q26.31-q27.3, and 20q11.21-q13.12; and two additional regions meeting criteria for suggestive significance at 7p14.1-p11.22 and 9p24.3. All five identified regions replicated previous findings, and for some of the regions, we were able to narrow the boundaries.…”

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer

“…126 In contrast with these disorders, there has been no strong evidence for linkage on chromosome 8p in any of the genome-wide linkage studies of autism. 127,128 Only one linkage analysis on multiplex autism families stratified according to delayed expressive speech found higher linkage signals in the delayed groups for some loci on chromosome 8p. 129 Given this linkage scenario, chromosome 8p should be considered as a robust candidate for a susceptibility region for schizophrenia especially with clinical features that bring to mind the classical dementia-praecox syndrome described by Emil Kraepelin.…”

Epigenetic remodelling and dysregulation of DLGAP4 is linked with early-onset cerebellar ataxia

“…The disruption of gene products that are highly expressed in Purkinje neurons is also associated with movement disorders including cerebellar ataxia (43) and is compatible with our finding that DLGAP4 gene products (mRNAs and protein) were abundant in human Purkinje neurons. Additionally, single nucleotide polymorphisms within the 20q11.21–q13.12 locus and comprising the DLGAP4 gene have been linked with the development of early onset autism spectrum disorders (44,45). Moreover, altered methylation patterns have been found in three CpG islands within the SHANK3 gene (coding for the SH3 and ankyrin domain containing protein, a known interaction partner of DLGAP4) (40), in post-mortem brain samples from autism spectrum disorder patients, which is accompanied with altered expression and alternative splicing of the SHANK3 gene (22).…”