It is now well established that genetic factors play an important role in the pathogenesis of autism disorder and converging lines of evidence suggest the implication of the X chromosome. Using a sample of subjects diagnosed with autism spectrum disorders, exclusively composed of males from French-Canadian (FC) origin, we tested markers covering the entire X chromosome using a family-based association study. Our initial analysis revealed the presence of association at two loci: DXS6789 (P=0.026) and DXS8043 (P=0.0101). In a second step, we added support to the association at DXS8043 using additional markers, additional subjects and a haplotype-based analysis (best obtained P-value=0.00001). These results provide support for the existence of a locus on the X chromosome that predisposes the FC to autism spectrum disorders.
Autism disorder (AD, MIM 209850) is a neurodevelopmental neuropsychiatric disorder characterized by behavioral impairments in three areas of child development: (1) social interaction, (2) verbal and nonverbal communication and imaginative play, (3) restricted interests and stereotypic play.1, 2, 3 This condition affects up to 1/1000 individuals4 with a male to female sex ratio of 4:1.5 AD is a clinical diagnosis based on criteria defined in the Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM IV); together with Asperger Syndrome and Pervasive Developmental Disorder Not Otherwise Specified (PDDNOS) it forms the category of Autism Spectrum Disorders (ASD). Research clearly substantiates the role of genetics in the etiology of ASD.6, 7
To date, several chromosomal loci have been suspected of harboring genes for ASD including loci on X chromosome.2, 8, 9 In fact, X chromosome contains genes which have already been linked to autism spectrum phenotype, the two-neuroligin genes, NLGN3 and NLGN4. Mutations were originally found in two families containing sib pairs affected with autism and Asperger. Mutation analysis in our AD cases, as well as those of other groups10, 11 did not reveal any causative variants in NLGN3 or NGLN4.10 This indicates that these two genes are responsible for only a small fraction of ASD cases. In addition, these genes may not be specific to the autism phenotype since mutations were also found in subjects having nonspecific mental retardation.12, 13, 14 Other X-linked disease genes like FMR1, MECP2 and ARX have been found to be mutated in autistic cases.14, 15, 16, 17 Again, these represent a small fraction of ASD cases. These data suggest that other locus on the X chromosome may play a role in the development of ASD. Since several independent candidate loci appear to exist on the X chromosome,9, 18, 19, 20, 21, 22 and much evidence suggest a role of X-linked genetic factors, in the present study we choose to examine the entire X chromosome for the search of a candidate locus in our population.
As previously mentioned, ASD affects males more than female (with a male to female ratio as high as 8:1 in Asperger syndrome); Although the reasons for such differential distribution between males and females is not entirely understood, it is possible that at least part of this may be due to X chromosome loci in a subgroup of patients. Schutz et al.23 reasoned that if an X-linked locus exists for AD or ASD, then affected males are more likely to represent a homogenous subgroup of individuals. Therefore, in order to reduce the genetic heterogeneity, we only included affected males with ASD in the present study.
In addition to increasing homogeneity by studying males only, we selected our probands from a population with a strong founder effect, which may provide advantages in the search for genes predisposing to complex conditions such as ASD. The existence of a founder effect in the French-Canadian (FC) population has been confirmed by many studies.24, 25, 26 The FC population is particularly well suited for genetic studies of heterogeneous diseases for several reasons, including: (1) the vast majority of FC are descendants of a small number of ancestors who came to Nouvelle-France (Canada) prior to 1760; (2) for socio-economic, religious and linguistic reasons, the descendants of these founders did not mix with other immigrants over three centuries; (3) there was significant sustained demographic growth of the population with doubling of the population every 25–30 years; and (4) detailed haplotyping of 10 cM segments of FC chromosomes has shown that there are few double recombinants, thus facilitating the use of haplotypes for fine mapping. Such founder effects help to reduce noise when searching for candidate genes in association studies.24, 25, 26 Ultimately, the advantage of using a more homogenous population in an association study is that it reduces the need for a large sample size and for multiple densely spaced markers.
To date, the majority of studies investigating X chromosome in ASD are linkage studies using multiplex families or affected sib-pair subjects. For this study, we chose a different approach: we used a sample of FC males trios (affected child and parents) to evaluate association over the entire X chromosome. This analysis was conducted in two steps. In Step I, we tested 13 microsatellite markers (spaced ∼10 Mb) selected on the basis of their relevant chromosomal location, including four markers previously reported to be linked with autism (DXS996, DXS7132, DXS6789 and DXS1047), in an initial set of 64 unrelated trios. In Step II, we added 21 FC males trios and additional markers at the most promising loci.
Subjects and methods
Subjects diagnosed with autism spectrum disorders and both of their parents were recruited from clinics specializing in the diagnosis of Pervasive Developmental Disorders (PDD), readaptation centers, and specialized schools in the Montreal and Quebec regions, Canada. Subjects with ASD were diagnosed by child psychiatrists and psychologists expert in the evaluation of ASD. Evaluation based on the DSM criteria included the use of the Autism Diagnostic Interview-Revised (ADI-R)27 and the Autism Diagnostic Observation Schedule (ADOS).28 As an additional screening tool for the diagnosis of ASD, the Autism Screening Questionnaire, which is derived from the ADI-R, was completed.29 Furthermore, all probands medical charts were reviewed by a child psychiatrist expert in PDD to confirm their diagnosis and exclude subjects with any comorbid disorders. Exclusion criteria were: (1) an estimated mental age <18 months, (2) a diagnosis of Rett Syndrome or Childhood Disintegrative Disorder and (3) evidence of any psychiatric and neurological conditions including: birth anoxia, rubella during pregnancy, fragile-X disorder, encephalitis, phenylketonuria, tuberous sclerosis, Tourette and West syndromes. Subjects with these conditions were excluded based on parental interview and chart review. However, participants with a co-occurring diagnosis of semantic-pragmatic disorder (due to its large overlap with PDD), attention deficit hyperactivity disorder (seen in a large number of patients with AD during development) and idiopathic epilepsy (which is related to the core syndrome of AD) were eligible for the study. As males do not inherit their paternal X chromosomes, patients for this study were classified as being FC when the maternal grand parents were of FC origin.
Blood samples were collected from each member of the nuclear families (subject, mother and father) followed by DNA extraction from lymphocytes using the Puregene reagents (Gentra System, USA). Microsatellite markers were obtained from the Marshfield genetic map (Center for Medical Genetics, Marshfield Medical Research Foundation) and primer sequences were obtained from the Genome Database (http://www.gdb.org/) and the UCSC Genome Bioinformatics site (http://genome.ucsc.edu/). The marker map positions were based on sex-averaged maps from the Marshfield Medical Research Foundation. Variable number tandem repeats (VNTR) were selected from the UCSC Genome Bioinformatics site and primers were designed as described above. PCR amplification for microsatellites and VNTR were performed in the presence of S35-dATP and amplicons were analyzed on 6% denaturing polyacrylamide gel, followed by autoradiography. Allele sizes were determined by comparison to an M13mp18 sequence ladder and numbered according to the Foundation Jean Dausset CEPH database. Single nucleotide polymorphisms (SNP) were chosen from public database and genotyping was performed at the McGill University and Genome Québec Innovation Centre (http://www.genomequebec.mcgill.ca/) on the Ultra-High Throughput Orchid platform. SNP-flanking sequences were tested for the presence of repeats or duplicated regions using the BLAT program (http://www.genome.ucsc.edu). PCR primers were designed using the Autoprimer program (http://www.autoprimer.com).
Mutational analysis of SLITRK2 and CXORF1
We sequenced both strands of the genomic sequence coding for all available exons (one exon for CXORF1 and five for SLITRK2), flanking splice junctions and untranslated regions (as shown in the University of California, Santa Cruz (UCSC: http://genome.ucsc.edu/) genome browser) of the CXORF1 and SLITRK2 genes. Primers were designed using genomic sequence information from UCSC genome browser and the Lasergene PrimerSelect program. The sequencing procedures for mutation detection were performed as published elsewhere. 30
Transmission disequilibrium test (TDT) and haplotype association tests were computed using TDTPHASE from UNPHASED software, a program written by Frank Dudbridge (UNPHASED, version 2.403; http://www.mrc-bsu.cam.ac.uk/personal/frank/software/unphased/).30, 31, 32 UNPHASED is a suite of programs for association analysis of multilocus haplotypes from phased and unphased genotype data. The programs extend previous methods to include haplotypes and missing genotypes and allow X chromosome data. In the case of X chromosome data from males, paternal genotype is ignored and only maternal genotypes are considered. All of the results presented in this study were performed without using the unphased haplotypes option in order to have the real representation of the sample haplotypes and statistics. The significance of each potential association is measured by a likelihood ratio statistic (LRS). Odds ratios (OR) were calculated using the program 2BY2 version 1.50 from Jurg Ott (Utility programs for analysis of genetic linkage, 1988–2001). P-values are derived from the Fisher's exact test and the TWO-SIDED P-value was considered. An OR of 1 implies that the allele is transmitted 50% of times, in average. An OR greater or lesser than one implies that the allele is significantly over- or undertransmitted to the affected subject, respectively. Linkage disequilibrium between markers (D′) was calculated using the program LDMAX for the input file followed by the use of the GOLD program (www.well.ox.ac.uk/asthma/GOLD). For all the analyses performed in the present study, corrections for multiple testing were not carried out. For graphic representation, LRS and P-value were converted to the –LOG 10 P-value.
A total of 255 individuals were included in the present study. This represents 85 nuclear families of FC origin. All probands were males and they all received a diagnosis of autism spectrum disorder (Autism=53, Asperger=21 and Pervasive developmental disorder not otherwise specified=11). Average age of the affected subjects was 13.1 years, with a range of 3.3–33.4 years.
Step I: X chromosome-wide individual marker association
TDT was performed using 13 markers (Table 1) in 64 unrelated ASD affected FC trios. The average heterozygosity of these 13 markers is 0.73 and the average genetic distance between contiguous markers is 7 cM. Evidence for association at marker DXS6789 (LRS=18.940, df=9, P=0.0257) and marker DXS8043 (LRS=20.06, df=8, P=0.0101) were found with the 64 FC trios (Table 2). For marker DXS6789, linked to ASD in previous studies,18, 21 a departure from random transmission is observed with two alleles (Table 2). Allele 3 (141 bp) is significantly overtransmitted to the affected proband, suggesting that it may be a risk allele. In contrast, allele 4 (137 bp) is undertransmitted suggesting a protective effect. For marker DXS8043, we also observed a pattern of overtransmission of allele 3 (167 bp) suggesting that this allele confers risk. Since DXS6789 (LOCUS Xq21.33) and DXS8043 (LOCUS Xq27.3) are 32 cM apart, we considered them as two independent loci. None of the other 11 markers was associated with ASD in this study sample.
Step II: fine mapping
To further analyze the associations at LOCUS Xq21.33 and LOCUS Xq27.3, we analyzed additional markers and added 21 newly recruited males. Markers were chosen according to their physical location.
In this second step, we added three markers; DXS6908, DXS8077 and DXS6799 at position 61.88, 62.52 and 64.41 cM, respectively. TDT analysis revealed suggestive association with marker DXS6799 (LRS=12.85, df=5, P=0.0248). This marker is 1.88 cM centromeric to DXS6789. Although the number of informative transmission is very modest, the only observed departure from random transmission is observed with allele 5 (Transmitted=1, nontransmitted=7, OR 0.13; CI: 0.02-1.07, P=0.00591).
In addition to microsatellite markers, LOCUS Xq27.3 was also further investigated with SNP because of the limited availability of microsatellites within the region. Since SNP are much less informative than repeats, we used several SNP to cover this candidate region (see Table 1, for markers used). Analysis of these additional markers revealed association with three SNP (rs232684, rs232686 and rs232707), which are telomeric to DXS8043 (Table 3). The most significant association is found with SNP rs232684 (LRS=6.641, df=1, P=0.00996). All of these three SNP represent a C to T transition. For all of them, allele C revealed an OR >5, suggesting that this allele from these three SNP may be associated with increased susceptibility to ASD.
In order to determine if we can detect a common susceptibility haplotype in the present sample of FC ASD males at LOCUS Xq21.33 and Xq27.3, we first determined Linkage Disequilibrium (D′) between contiguous pairs of markers tested at both loci. Markers in LOCUS Xq21.33 do not show any evidence of LD (data not shown). However, at LOCUS Xq27.3, values of D′>0.8 are observed for several pairs of markers (see Figure 1). Consequently, for the LOCUS Xq27.3 markers in LD, we tested different combinations of marker haplotypes using the sliding window approach. Looking at the haplotype combination and considering only heterozygous mothers for the haplotypes, a chromosomal region composed of seven markers (rs1415636–rs1339486–rs232684–rs232686–DXS8045–rs232695-rs232707), and highly in LD, showed a significant departure from random transmission. Within this region, several haplotypes windows gave positive values, with the most significant associations being represented in Table 4. Among these, three haplotypes showed a P=0.00001. Transmission of these haplotypes represents almost half of subjects harboring these haplotypes.
Within the associated LOCUS Xq27.3, only two annotated genes lie in that region, SLTRK2 and CXORF1. In addition to their physical location, these genes are of interest as they are mainly brain expressed in region reported to be affected in ASD. While the function of CXORF1 is not yet known, SLTRK2 is involved in the synaptogenesis. We therefore sequenced in both directions the genomic sequence of these two genes, in eight affected patients and two healthy controls. Patients included in this screening had the largest most common overtransmitted haplotype (Table 4: haplotype #7). No mutations were found in any of these subjects.
To our knowledge, this is the first family-based association study looking at the entire X chromosome. In the present study we have identified two potential associations between FC autistic families and markers on the X chromosome. Marker DXS6789 is already known to be associated with autism18, 21 and our results add further support for its implication in ASD. Whereas we found a modest association with one individual marker, the limited number of markers used and the physical position of these markers did not allow us to conduct a haplotype analysis (LD (D′) <0.04, data not showed). Genotyping more markers within this locus is needed to further analyze it possible role in ASD.
LOCUS Xq27.3 represents the most significant association in the present study. Interestingly, two independent studies reported positive linkage at this region. Yonan et al.22 found a proximal linkage (X-MLS=1.78) with 345 analyzed multiplex families. More recently, Vincent et al.9 using 22 families found a modest linkage with two markers (MLOD=1.3, P=0.01, and MLOD=1.7, P=0.005), which are centromeric and telomeric to our associated region. While for both group their linked region is quite large our genomic segment found to be most significantly associated with ASD in the present study is quite small, representing 274 kb (according to the UCSC Genome database). Interestingly, the most associated single marker allele, rs232684, is in the core of the haplotypes shown in Table 4. This polymorphism is not part of any predicted mRNAs and ESTs and the C is not conserved across species, which suggest that rs232684 is not a functional polymorphism. According to public databases, the associated genomic segment is a gene poor region. In fact, the region contains no annotated genes. However, several human ESTs and two human mRNAs are present in the interval. Among these, only one mRNAs, BC040297, overlaps with a predicted transcript, named ‘flerju’. In addition, the region contains many non-human mRNAs and several conserved regions between human and other species. However, these are not overlapping with human ESTs or human mRNAs suggesting that they might not be real genes.
As we expected to find a large common region in the founder population, the identification of a relatively small associated region (274 kb) suggests that the susceptibly haplotype may be older than the founding of FC population. Consequently, many recombination events would have occurred before the establishment of the population in Quebec. The detection of association at two loci in the same cohort of subjects raises the possibility of multiple hypotheses; among these are (1) the possibility that two ancestral mutations have been introduced in the FC population or (2) that one of the associations may be a false positive at one locus. In order to confirm that this haplotype is a common susceptibility haplotype for ASD, it will need to be replicated in other population.
We have looked at the sequence of two annotated genes, SLITRK2 and CXORF1, which are centromeric to the associated haplotype. While the function of CXORF1 is not clear,33 the gene product is found mainly in the hippocampus, particularly in the granular-cell layer of the dentate gyrus, a brain region reported to be involved in autism.34, 35 SLITRK2 is a neuronal transmembrane protein which controls neurite outgrowth.36, 37 These genes are candidates for ASD; however, no mutation was found. Our negative mutational analysis results are consistent with the fact that they are located outside of the associated genomic segment. However, the small number of patients screened and the fact that the regulatory regions of these genes were not analyzed do not allow us to exclude them as candidate for ASD.
The present study presents different limitations and the results should be interpreted with caution. No correction for multiple testing has been performed. Moreover, association studies are known, especially when using multiple marker tests, to produce false positive results. These results need to be replicated in an independent FC autistic cohort as well as non-FC cases. We are currently collecting additional samples to replicate our results.
In conclusion, our data supports the existence of two candidate loci on the X chromosome.
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We thank all the families who made this research possible by participating in our study. Claude Marineau and Dr Lan Xiong for helpful discussions and comments. Thanks to Dominique Verlaan for carefully reading the manuscript. We also thank Daniel Rochefort for technical help. This work was supported by the Canadian Institutes for Health Research.
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Cite this article
Gauthier, J., Joober, R., Dubé, M. et al. Autism spectrum disorders associated with X chromosome markers in French-Canadian males. Mol Psychiatry 11, 206–213 (2006). https://doi.org/10.1038/sj.mp.4001756
- autism spectrum disorders
- association study
- X chromosome
- haplotype analysis
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