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Background: Synaptic genes, NLGN3 and NLGN4X, two homologous members of the neuroligin family, have been supposed as predisposition loci for autism spectrum disorders (ASDs), and defects of these two genes have been identified in a small fraction of individuals with ASDs. But no such rare variant in these two genes has as yet been adequately replicated in Chinese population and no common variant has been further investigated to be associated with ASDs. Methods: 7 known ASDs-related rare variants in NLGN3 and NLGN4X genes were screened for replication of the initial findings and 12 intronic tagging single nucleotide polymorphisms (SNPs) were genotyped for case-control association analysis in a total of 229 ASDs cases and 184 control individuals in a Chinese Han cohort, using matrix- assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Results: We found that a common intronic variant, SNP rs4844285 in NLGN3 gene, and a specific 3-marker A G T haplotype X -X -X (rs11795613-rs4844285-rs4844286) containing this individual SNP were associated with ASDs and showed a male bias, even after correction for multiple testing (SNP allele: P = 0.048, haplotype:P = 0.032). Simultaneously, none of these 7 known rare mutation of NLGN3 and NLGN4X genes was identified, neither in our patients with ASDs nor controls, giving further evidence that these known rare variants might be not enriched in Chinese Han cohort. Conclusion: The present study provides initial evidence that a common variant in NLGN3 gene may play a role in the etiology of ASDs among affected males in Chinese Han population, and further supports the hypothesis that defect of synapse might involvement in the pathophysiology of ASDs. Background syndrome and pervasive developmental disorder not Autism spectrum disorders (ASDs; MIM 209850) are otherwise specified (PPD-NOS) , which were concep- acknowledged to be among the most heritable neurode- tualized as a spectrum of disorders occurring on a conti- velopmental disorders with onset prior to age 3, which nuum with a great diversity of symptom and varying characterized by impaired reciprocal social interactions, degrees of severity. Asperger syndrome is diagnosed when lacks delays in cognitive development and lan- deficient communication, restricted interests and stereo- typed activity patterns (American Psychiatric Associa- guage, and PDD-NOS is diagnosed when full criteria for tion, 2000). ASDs present a broadly defined disorders of the other two disorders are not met . behavior and cognition, including autism, Asperger It is now well established that ASDs are etiologically heterogeneous, probably associated with a combination of the effects of genetic and environmental causes [3-5]. * Correspondence: email@example.com The strong role of genetic factors in the pathogenesis of Department of Pediatric Health Care, Children’s Hospital, Zhejiang University ASDs has been definitely recognized, but still difficult School of Medicine, Hangzhou, China Full list of author information is available at the end of the article © 2011 Yu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 2 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 completely comprehended. Approximately 10-20% of NLGN4X gene in three autistic females . Then ASDs cases are already identified to be attributable to Jamain et al.  first demonstrated the evidence for a genetic syndromes with highly penetrant chromosomal pathogenic effect of neuroligins in ASDs, who identified abnormalities, known rare mutations, and copy number a missense mutation (R451C) in NLGN3 and a frame- variants (CNVs) , but the causes of the majority of shift mutation (1186insT) in the homologous gene ASDs cases remain further determined and the biological NLGN4X in two Swedish families in each case one brother with typical autism and the other with Asperger basis remains pooly understood. Thus, neuroscience Syndrome. The mutant proteins were considered signifi- research efforts have focused on elucidating the neuro- cantly retained in the endoplasmic reticulum with biological basis of ASDs, and a growing body of evidence indicates that ASDs are brain development disorders reduced protein expression and/or adhesive activity to occuring during prenatal and postnatal period, and to impair their function in the synaptogenesis compared put forward the possibility that the neuropathology of with the wild-type neuroligin proteins [17,18]. Later, a ASDs may present an on-going process extending 2-bp deletion (1253delAG) encoding a truncating through early childhood and into adulthood [6,7]. More- NLGN4X protein (D429X) was detected in all indivi- over, histological studies on post-mortem brains have duals affected with mental retardation within a large also revealed that neurons from autistic patients exhibit a French family , providing the evidence that rare reduction of GABA production, dendrite branching and mutations of these two neuroligin genes seem to contri- arborization. Considering the fact that the normal func- bute to developmental delay and ASDs. Animal model tions of brain depend on proper working of the diverse studies showed that mice carrying the R451C mutation synaptic components distributed in various compart- of NLGN3  or a deletion of NLGN4X  caused ments of the synapse, which is specialized site of cell-cell an increase in inhibitory synaptic activity and exhibited contact allowing communication between neurons, the behavioral phenotypes characteristic of ASDs due to synaptic hypothesis was proposed that abnormalities at protein misfolding , highlighting a possible role for the synapse may contribute to development of brain dis- excess inhibitory neurotransmission in ASDs. In addi- orders such as ASDs and mental retardation. A genetics ton, the specific NLGN3 mutation has also been consid- topic in ASDs has emerged focusing on identification of ered to affect information processing in neuronal the synaptic genes contributing to the formation and networks by altering network architecture and syn- function of the synapse. The synaptic hypothesis was also chrony in a recent report . Afterward, further genetic rare variants, including non-synonymous muta- confirmed by the discovery of mutations in trans-synap- tions and splice variants, in the NLGN4X gene were tic adhesion proteins, such as neuroligins and neurexins, in a small fraction of individuals with ASDs, which was detected in probands with autism, mental retardation or proposed to alter synaptic homeostasis and/or impair pervasive developmental disorders-not otherwise speci- synapse development [8,9]. fied (PDD-NOS) in following replication studies [24-27]. It is striking that ASDs show markedly skewed in sex In contrast, controversial results obtained from several distribution with approximately four times more frequent replication studies failing to detect neuroligin variants in in male than female, together with the view that some of samples of individuals with ASDs from different popula- X-chromosomal genes may be involved in human neu- tions [28-31]. Moreover, no evidence was found for ropsychiatric disorders (X-linked disorders) , specu- involvement of NLGN3 and NLGN4X with high-func- lating that X chromosome may be of importance for the tioning ASDs in a 2008 study . These results indi- development of this condition. Many independent gen- cate that these rare mutations may be responsible for a ome-wide scans for ASDs susceptibility loci have also small fraction of events and should been widely repli- demonstrated that X chromosome may contain more cated and validated by other independent studies with than one ASDs susceptibility genes. Two X-linked neuro- different genetic background. ligin genes, neuroligin 3 (NLGN3) and neuroligin 4X Meanwhile, there is emerging evidence indicating that (NLGN4X) were therefore considered as good functional the genetic etiology of complex traits of ASDs is likely to and positional candidate for predisposition to ASDs and be based on a combination of multiple rare and common have been screened for mutations in multiple studies. susceptibility loci. And common variants in susceptibility Neuroligins are cell adhesion molecules localized post- genes are also of importance for majority individuals, synaptically in the glutamatergic synapses, and interact although exerting merely a modest or small effect sizes contributing to the genetic background of diseases . with presynaptic neurexins  to form heterophilic However, little such variants in NLGN3 and NLGN4X complex, which likely play an critical role in synaptic gene have as yet been proven beyond doubt to be asso- transmission and differentiation of synaptic contacts [12-14]. The role of neuroligins in ASDs was implicated ciated with ASDs . So it is important to search for in discovery deletions of Xp22.1 containing the additional common variants for a better understanding of Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 3 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 the genetic modulators of these two neuroligin genes Rare Variants Screening and SNPs Genotyping responsible for ASDs susceptibility. Genomic DNA was extracted from venous blood sample In the present study, we therefore attempted to repli- using AXYGEN DNA extraction kit (AxyPrep Blood cate known rare variants in NLGN3 and NLGN4X genes Genomic DNA Miniprep Kit, USA), according to the to validate the initial findings and determine their fre- manufacture’s recommended protocol. Rare variant screening and SNPs genotyping were performed using quencies in Chinese Han population, and further per- matrix-assisted laser desorption/ionization time-of-flight formed a case-control association analysis of tagging (MALDI-TOF) mass spectrometry (Sequenom Inc., San SNPs within these two neuroligin genes to evaluate if Diego, California) and analyzed with the SpectroTYPER common variants also play a potentially role for etiology of ASDs. RT 2.0 software. A routine quality control procedure to assess genotyping reproducibility was performed by Methods repeating 10% of samples selected randomly. Subjects Subjects recruited in our study consisting of 229 unre- Statistic analysis lated patients with ASDs and 191 ethnically and geogra- Considering highly varying prevalence in female and male phically matched controls in Chinese Han cohort. All patients of ASDs, we separate subjects by gender into case affected subjects (mean age: 5.5 years, 83.4% males, and control subgroups. The Hardy-Weinberg equilibrium 16.6% females) were from outpatients of Children’s Hos- (HWE) for SNP markers on the X chromosome can be pital, Zhejiang University School of Medicine and from examined by testing two null hypotheses: H1: allele fre- several special autism-training schools, which were diag- quencies between males and females are equal and H2: nosed using the diagnostic and statistical manual of HWE holds in females . A basic association of allele mental disorders (DSM-IV) criteria or International frequencies was analyzed in PLINK version 1.07 software Classification of Diseases-10 (ICD-10) by an experienced (http://pngu.mgh.harvard.edu/purcell/plink/; Purcell et al, psychiatrist. In the present study, a relatively homoge- 2009)  and corrected by Bonferroni’sapproach for neous sample of ASDs with typical phenotype was taken multiple testing as the most stringent test to control false- in to reduce heterogeneity. Clinical assessment and phy- positive results. The crude odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated for the sical examination were obtained and the molecular tests effects of high-frequency allele in the case group. Pair-wise were performed to exclude the patients with fragile X linkage disequilibrium (LD) between the different markers syndrome and tuberous sclerosis, or any kind of medical was estimated by the D’ and r , using Haploview version conditions suspected to be associated with ASDs. The controls (mean age: 3.2 years, 74.3% males, 25.7% 4.2 software (http://www.broad.mit.edu/mpg/haploview females) sharing the same ethnical background with the Barrett et al., 2005)  with visualized structure. Haplo- affected subjects were unrelated Chinese individuals type blocks within each gene were defined by the default who had visited our hospital to evaluate their health sta- algorithm of Gabriel method  and haplotype frequen- tus. They were clinically assessed to confirm the absence cies were estimated with the expectation maximization of both personal and family history of major neuropsy- (EM) algorithm, excluding haplotypes with frequencies chiatric disorders. The study was approved by Ethics lower than 5%. While for X-linked SNP in male samples, Committee of Zhejiang University and written informed genotype of each SNP was interpreted as homozygous A A B B consents were obtained from parents or legal guardians (genotype X X or X X ), although the male X was hemi- A B for their participating in the study. zygous (genotype X or X ). The exact P-values with 10,000 permutations were done for multiple test correc- Selection of rare mutations and SNPs tion of the observed haplotype association. The differences 7 known rare variants in NLGN3 and NLGN4X genes were considered statistically significant with P < 0.05. previously reported to be associated with ASDs were Post-hoc power analysis was implemented using the com- chosen for rare variant screening (Table 1). The tagging puter G*Power. SNPs were selected based on pair-wise r method (para- SNPs were removed from analysis if they had the per- meter: r ≥ 0.8) using SNPbrowser software. Based on centage of non-missing genotypes less than 0.95, dis- the genotype data from the SNP databases http://www. played Hardy-Weinberg disequilibrium (P < 0.05), or ncbi.nlm.nih.gov/snp/, 12 validated and suitable tagging had a minor allele frequency (MAF) < 0.05. SNPs within NLGN3 and NLGN4X genes (Table 2) with Results a minor allele frequency (MAF) greater than 5% in the Rare variants analysis Han_Chineseorinthe HCB_Asianpopulationwere None of these 7 rare variants in NLGN3 and NLGN4X selected to capture the majority of the common varia- genes previously known to associated with ASDs was tions for case-control association analysis. Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 4 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 Table 1 Summary and results of previously known rare variants in NLGN3 and NLGN4X gene Gene Sequence Amino-acid Mutation type Position in Occurrence in ASDs/total Occurrence in controls/total variant change gene ASDs** controls** NLGN3 c.C1351T R451C Missense Exon 6 0/229 0/188 mutation NLGN4X c.1186insT D396X Frameshift Exon 5 0/227 0/190 mutation c.1253delAG D429X Frameshift Exon 5 0/229 0/190 mutation c.759G > A G99S Missense Exon 3 0/229 0/191 mutation c.1597A > G K378R Missense Exon 6 0/227 0/191 mutation c.1671G > A V403M Missense Exon 6 0/229 0/191 mutation c.2574C > T R704C Missense Exon 7 0/229 0/189 mutation **due to uncertainties, some sites were miss-identified for several samples, even by repeating. replicated neither in our patients with ASDs nor con- generated by the default algorithm of Gabriel method trols (Table 1). (Figure 1). In male subgroup, a significant association was observed for the three-marker haplotype block Single nucleotide polymorphisms (SNPs) analysis (rs11795613-rs4844285-rs4844286, global P value = The genotypic distribution displayed no deviation from 0.032) containing the individual SNP rs4844285 asso- Hardy-Weinberg equilibrium (P > 0.05) (data not ciated with male ASDs in the allelic-wise analysis. The A G T shown). Allelic frequencies and association findings of most frequent haplotype X -X -X was significantly all these SNPs between patients with ASDs and controls more frequent in male patients with ASDs when com- in primary and sex-specific analyses have been summar- pared to male controls (P = 0.009) and the diference ized in Table 2. Pair-wise linkage disequilibrium (LD) remained after permutation testing (P = 0.017), which per A G T between SNPs within each gene was calculated for suggested that the haplotype X -X -X playaroleasa males and females separately, and D’ and r values for susceptibility factor for ASDs (OR = 1.834, 95% CI: all possible pairs were shown in Figure 1. Haplotype 1.158-2.907). In female subgroup, one two-marker haplo- blocks generated by the Gabriel method were also type block (rs11795613-rs4844285) showed significant shown in Figure 1. The results of the association analy- association with ASDs (global P value = 0.035). The hap- A G sis based on haplotype for each gene were summarized lotype X -X was significantly more frequent in patients in Table 3. with ASDs compared with controls acting as a suscept- As shown in Table 2, nominally significant differences ibility factor for ASDs (P = 0.035, OR = 2.147, 95%CI: G A of allele frequencies were detected for three SNPs in 1.048-4.400), while the haplotype X -X was more fre- NLGN3 gene in total samples contrasted between indivi- quent in controls likely acting as a protective factor duals with ASDs and controls and these differences against ASDs (P = 0.035, OR = 0.446, 95%CI: 0.227- remained significant after Bonferroni correction for mul- 0.954). These results did not survive 10,000 times permu- tiple testing. Giving the higher prevalence rate of ASDs tation testing. in males than in females, we performed a secondary case- For NLGN4X gene, nominal significant difference in control analysis across all of SNPs stratified by sex. The allelic frequency of SNP rs5916397 was detected between sex-specific analysis showed that the significant differ- the female individuals with ASDs and controls (P = 0.047). ences of these three SNPs were almost entirely account The rs5916397-X allele was overrepresented in female for association with affected males. While only one SNP individuals with ASDs (OR = 2.133, 95% CI = 1.001-4.545) rs4844285 remained the evidence of significant associa- while this difference disappeared for Bonferroni correc- tion after Bonferroni correction testing (P = 0.048) tion. Although no haplotype block containing this SNP corr and the rs4844285-X allele had an increased risk for was detected by the Gabriel method, this SNP was in rela- male with ASDs (OR = 1.872, 95% CI:1.175-2.981). Pair- tively high LD with rs6529901 (D’ > 0.8) and was available wise linkage disequilibrium (LD) revealed that the six for the multimarker analysis. The result showed that no SNPs analyzed were in high LD (D’ > 0.8), and there were association was observed for this two-marker haplotype one three-marker haplotype block in male subgroup and (rs6529901-rs5916397) both in males and females (males: two two-marker haplotype blocks in female subgroup global P value = 0.580, females: global P value = 0.145), Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 5 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 Table 2 Allelic frequencies and case-control association analysis with ASDs in the primary and sex-specific analyses within the NLGN3 and NLGN4X genes Total samples (N = 420) Male samples (N = 333) Female samples (N = 87) Genes SNP Position Assoc Allele Allele P P OR Allele Allele P P OR Allele Allele P P OR corr corr corr in gene Allele counts in counts in value value (95%CI) counts in counts in value value (95% counts in counts in value value (95% controls cases(%) controls cases(%) CI) controls cases(%) CI) (%) (%) (%) NLGN3 rs11795613 Intron1 X 150(62.5%) 199 0.0035 0.021 1.756 84 (59.2%) 137 0.0163 ns 1.752 66 (67.3%) 62(81.6%) 0.035 ns 2.147 (G/A) (74.5%) (1.201- (71.7%) (1.106- (1.048- 2.567) 2.774) 4.4) rs4844285 Intron2 X 149(62.6%) 201 0.0016 0.0097 1.847 83 (59.3%) 139 0.0079 0.048 1.872 66 (67.3%) 62(81.6%) 0.035 ns 2.147 (A/G) (75.6%) (1.259- (73.2%) (1.175- (1.048- 2.711) 2.981) 4.4) rs4844286 Intron2 X 163(67.9%) 206 0.0196 ns 1.595 95 (66.9%) 145 0.07 ns 1.559 68 (69.4%) 61(80.3%) 0.104 ns 1.794 (G/T) (77.2%) (1.076- (75.9%) (0.963- (0.882- 2.365) 2.525) 3.648) rs5981079 Intron2 X 132(55.5%) 175 0.0079 0.047 1.634 79 (55.6%) 126 0.041 ns 1.595 53 (55.2%) 49(68.1%) 0.092 ns 1.728 (C/T) (67.0%) (1.136- (66.7%) (1.019- (0.913- 2.35) 2.497) 3.272) rs7051529 Intron4 X 132(58.9%) 182 0.025 ns 1.528 73 (56.2%) 125 0.093 ns 1.479 59 (62.8%) 57(77.0%) 0.047 ns 1.989 (G/A) (68.7%) (1.054- (65.4%) (0.936- (1.003- 2.217) 2.336) 3.943) rs10127395 Intron5 X 196(81.7%) 221 0.676 ns 1.102 117(82.4%) 158 0.855 ns 1.055 79 (80.6%) 63(82.9%) 0.700 ns 1.166 (G/T) (83.1%) (0.698- (83.2%) (0.594- (0.535- 1.743) 1.875) 2.541) NLGN4X rs6529901 Intron3 X 129(55.8%) 150 0.827 ns 1.04 82 (58.2%) 104 0.535 ns 0.87 47 (52.2%) 46(62.2%) 0.201 ns 1.503 (G/A) (56.8%) (0.729- (54.7%) (0.56- (0.804- 1.485) 1.351) 2.812) rs5961397 Intron3 X 176(73.6%) 198 0.895 ns 1.027 106(75.2%) 134 0.312 ns 0.776 70 (71.4%) 64(84.2%) 0.047 ns 2.133 (G/A) (74.2%) (0.69- (70.2%) (0.475- (1.001- 1.528) 1.27) 4.545) rs4370667 Intron2 X 183(80.6%) 212 0.864 ns 0.962 112(81.8%) 150 0.592 ns 0.859 71 (78.9%) 62(81.6%) 0.665 ns 1.185 (C/T) (80.0%) (0.616- (79.4%) (0.491- (0.549- 1.502) 1.501) 2.559) rs10522049 Intron2 X 198(82.8%) 223 0.839 ns 1.049 114(80.9%) 157 0.754 ns 1.094 84 (85.7%) 66(86.8%) 0.831 ns 1.1 (G/A) (83.5%) (0.658- (82.2%) (0.625- (0.46- 1.35) 1.914) 2.634) rs1882409 Intron1 X 69(29.0%) 82(30.7%) 0.673 ns 1.086 42 (30.0%) 59(30.9%) 0.862 ns 1.043 27(27.6%) 23(30.3%) 0.695 ns 1.141 (A/G) (0.741- (0.649- (0.590- 1.591) 1.676) 2.208) rs5916352 Intron1 X 184(77.0%) 215 0.187 ns 1.339 34 (24.1%) 32(17.1%) 0.117 ns 0.65 21 (21.4%) 16(21.1%) 0.952 ns 1.023 (G/C) (81.7%) (0.867- (0.378- (0.492- 2.067) 1.117) 2.128) Assoc Allele, associated allele; OR, odds ratio; 95%CI, 95% confidence interval; P value, corrected by Bonferroni’s approach for multiple testing, ns, not significant. Male samples (n = 333) include 191 cases and 142 corr controls, female samples (n = 87) include 38 cases and 49 controls. Significant P-values are indicated in bold. Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 6 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 Figure 1 LD of the SNPs of NLGN3 and NLGN4X genes. The LD value (D’ and r ) within each diamond was computed using Haploview. The dark gray diamonds indicate strong evidence of LD for no historical recombination, while the white diamonds indicate strong evidence of LD. The confidence bound values of the light gray diamonds are between the valves reflected in the dark and white diamonds. Haplotype blocks by the Gabriel method are shown also. A: LD of the SNPs of NLGN3 gene with D’ and r values for males, B: LD of the SNPs of NLGN3 gene with D’ 2 2 2 and r values for females, C: LD of the SNPs of NLGN4X gene with D’ and r values for males, D: LD of the SNPs of NLGN4X gene with D’ and r values for females. G G even though the haplotype X -X was significantly more level of 0.05. Of the haplotype frequencies of frequent in controls compared to patients with ASDs in rs11795613-rs4844285-rs4844286, the used sample size female subgroup (P = 0.024, OR = 0.404, 95%CI: 0.18- had a 37.5% power to detect a small gene effect (corre- 0.904). In addition, another two-marker haplotype block sponding to 0.1) and a 99.9% power to detect a medium (rs1882409-rs5916352) was identified in male subgroup gene effect (corresponding to 0.3) at the alpha level of showing significant difference between patients with ASDs 0.05 (data not shown). A C and controls (global P = 0.035), and haplotype X -X was significantly more frequent in male ASDs compared to Discussion male controls (P = 0.023, OR = 2.546, 95%CI: 1.112- Our present results do lend support for the hypothesis 5.832), while the difference disappeared after permutation that a common variant in the NLGN3 gene (SNP test. rs4844285) may influence the susceptibility for male ASDs.Toourknowledge,this candidate gene study Power analysis represents a focus association study of common variants We estimated the statistical power using the G*Power of neuroligin genes in etioloty of ASDs, although pre- program, based on the method of asymptotic noncentral- vious studies have provide evidence of rare mutations of ity parameters for case-control association studies. Post- NLGN3 and NLGN4X genes causing to ASDs. Using a hoc power analysis showed that the used sample size had relative homogenous samples and a case-control based a 53.6% power to detect a small gene effect (correspond- design, we found that an intronic SNP rs4844285 in ingto 0.1)anda99.9% powertodetectamediumgene NLGN3 gene and a specific 3-marker haplotype block effect (corresponding to 0.3) of the allele frequencies of (rs11795613-rs4844285-rs4844286) were associated with SNP rs4844285 for a significant association at the alpha ASDs and showed a male bias after multiple correction, Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 7 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 Table 3 Haplotype blocks frequencies and case-control association analysis with ASDs within the NLGN3 and NLGN4X genes Gene Samples Haplotype Freqency in Freqency in Global P c Individual P P OR (95%CI) per Sequence controls cases value value value NLGN3 Males Block1: rs11795613-rs4844285-rs4844286 A G T X -X -X 0.579 0.716 0.032 6.74 0.009 0.017 1.834 (1.158- 2.907) G A G X -X -X 0.321 0.226 3.729 0.053 0.098 0.618 (0.378-1.009) G A T X -X -X 0.079 0.042 1.975 0.160 0.462 0.515 (0.202-1.317) Females Block 1: rs11795613-rs4844285 A G X -X 0.673 0.816 0.035 4.458 0.035 0.08 2.147 (1.048- 4.400) G A X -X 0.327 0.184 4.458 0.035 0.08 0.446 (0.227- 0.954) Block 2: rs4844286-rs5981079 T T X -X 0.557 0.678 0.221 2.573 0.109 0.244 1.671 (0.895-3.121) G C X -X 0.306 0.197 2.64 0.104 0.242 0.557 (0.274-1.133) T C X -X 0.137 0.125 0.044 0.834 0.996 0.902 (0.370-2.199) NLGN4X Males Block 2: rs1882409-rs5916352 G C X -X 0.700 0.695 0.035 0.009 0.925 1 0.977 (0.607-1.575) A G X -X 0.243 0.171 2.557 0.110 0.244 0.644 (0.374-1.107) A C X -X 0.057 0.134 5.17 0.023 0.068 2.546 (1.112- 5.832) Females Block 1**: rs6529901-rs5916397 A A X -X 0.514 0.595 0.145 1.122 0.290 0.665 1.386 (0.756-2.539) G A X -X 0.200 0.247 0.557 0.456 0.831 1.315 (0.641-2.697) G G X -X 0.269 0.129 5.083 0.024 0.060 0.404 (0.180- 0.904) OR, odds ratio; 95%CI, 95% confidence interval. P value, p value with 10,000 times permutation test. The haplotypes with frequencies lower than 5% excluded per from analysis. Block 1**, the two SNP, rs6529901 and rs5916397, was in relatively high LD with D’ > 0.8 and regarded as a block for multiple-marker analysis in this study. Significant p-values are indicated in bold. which was consistent with the fact that the prevalence were shown to be sufficient to trigger the formation of rate of ASDs in males is higher than that in females. new presynaptic architecture and induce the functional Simultaneously, further evidence was obtained for the presynaptic differentiation in vitro . So, it was specu- fact that these known rare mutations in NLGN3 and lated that genetic variants in these neuroligin genes may NLGN4X genes may be not enriched in subjects with be associated with neurodevelopmental disorders, such ASDs in Chinese Han cohort. as autism and Asperger syndrome, with a combination The neuroligin 3 gene (NLGN3) and neuroligin 4X of rare variants having a dramatic effect in fewer indivi- gene (NLGN4X), localized on Xq13.1 and Xp22.33, duals and common variants having small increments of encode a member of a family of neuronal cell surface risk in majority individuals. To date, only rare variants proteins serving as splice site specific ligands for neurex- of these two neuroligin genes have been soundly estab- ins and may be involved in the formation, organization lished risk for ASDs responsible for a small fraction of and remodeling of central nervous system synapses. The events, while no common variant was available for sus- encoded proteins were localized postsynaptically and ceptible to ASDs. For this reason, it is the most Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 8 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 interesting finding in our present study that a common differentially regulated genes on the autosomes are inte- variant in the NLGN3 gene was identified to be strongly grally involved in normal sex-specific brain development associated with susceptibility to male ASDs. The [41-43]. Evidences from multiple studies which have iden- NLGN3 gene is composed of eight exons with the start tified a major male-specific linkage peak at chromosome codon in exon2  and the SNP rs4844285 implicated 17q11 [44,45]. Although to what extent these regulatory was an intronic common variant localizing in the intron effects may ultimately relate to normal male and female 2ofthe NLGN3 gene with unknown function. Our brain development remains unclear, it is obvious that result showed that this SNP appeared to be most pro- there are substantial differences between the sexes at the molecular level. So, it is possible that NLGN3 may be cau- nounced associated with an increased risk for ASDs among affected males after multiple testing corrections sative gene for male predominance of ASDs. Another pos- (P = 0.048), with rs4844285-X as risk allele (OR = sible explanation is that the power to detect the observed corr 1.872, 95%CI:1.175-2.981). The finding was further sup- difference reduces due to the small sample size of females ported by the multimarker analysis, which also showed, in our present study. So, our sex-specific analyses were in male subjects, one three-marker haplotype block exploratory and require confirmationinadditional (rs11795613-rs4844185-rs4844286) containing this indi- samples. vidual SNP was vulnerable to ASDs (global P value = Several notions of this study should be considered for A G T 0.032) and the most frequent haplotype X -X -X was this association. First, the tagging SNPs analyzed were susceptible (P = 0.009, OR = 1.834, 95% CI: 1.158- unable to comprehensively cover the common variants 2.907). However, how this specific intron relates to across the both genes and other SNPs which were not ASDs maybepossiblethatthisintronicSNP do not selected in our present study may be associated with change gene function and a yet unidentified causal SNP ASDs, further analysis on the basis of detailed SNPs cov- may be linked to this haplotype and/or lies within or erage of these genes are necessary. In addition, all of the very close to the region spanning rs11795613 and SNPs investigated in the present study exist in introns 4844286, or a possibility of this intronic SNP playing with unknown function and could not be regarded to be pivotal roles in gene regulation. In addition, although causally related to ASDs but rather is likely to be in link- nominally significant differences were detected for this age disequilibrium with an as yet untested, functional SNP among female samples both in single SNP and hap- variant. Second, there were different haplotype blocks lotype analysis, the differences did not survive multiple generatedbetween themaleand female groupbythe testing corrections. The similar finding was obtained default algorithm of Gabriel method due to small differ- from another SNP rs5916397 of NLGN4X gene in ence of LD (D’ and r value) between pair-wise SNPs for female subjects, which showed nominal significant dif- different gender. Third, the Bonferroni correction was G G ference in allelic frequencies and haplotype X -X used for multimarker testing in our present study. It (rs6529901-rs5916397) between the female ASDs and would be overly conservative for non-independent tests. G G controls (allelic: p = 0.047, Haplotype X -X :p= Fourth, the average age of subjects was not well matched 0.024), while this results disappeared for multiple cor- between the controls and ASDs in the present study. rection. It was implicated that these SNPs may not However, this should not be regarded to have a marked make a statistically significant contribution to ASDs sus- affect on the results, since genetic nature of SNP is gen- ceptibility in our female samples. erally unlikely to change with age. It was of particular meaningful that our result of associa- Apart from this, rare genetic variants of susceptible tion of SNP rs4844285 in NLGN3 gene with ASDs exhib- genes are being increasingly discoveried as etiological fac- ited a male bias. Because of the overrepresentation of tors in ASDs. But most instances, rare mutations of males in samples with ASDs, as well as evidence for sex- NLGN3 and NLGN4X genes have not yet been widely specific effects on X chromosome, we hypothesized that replicated and systemically validated by other indepen- stratifying by gender may reduce genetic heterogeneity at dent studies within different population. Seeking replica- these two X-linked neuroligin loci. One possible explana- tion in other ASDs samples is important to confirm the tion of sex-specific association is that the underlying causative nature of these mutations and to determine genetic modulators for ASDs may differ with gender. their frequency. In our present study, we sought to repli- Indeed, a large body of researches have accumulated evi- cate the 7 known rare variants associated with ASDs in dences that male and female brains develop differently not both genes from Chinese Han population and revealed only in function field, but also that this sexual dichotomy no mutations or rare variants. This lack of replication of extends to the macroscopic structures of the brain. There- rare variants of these two genes in our samples may be for, genes located on the X chromosome and those genes due to greater heterogeneity across different ethnic popu- directly related to the function of sex-related hormones lation, and highlights the fact that these known rare mutations may be not enriched in patients with ASDs in are clear candidates. There is also increasing evidence that Yu et al. Behavioral and Brain Functions 2011, 7:13 Page 9 of 10 http://www.behavioralandbrainfunctions.com/content/7/1/13 8. Bourgeron T: A synaptic trek to autism. Curr Opin Neurobiol 2009, Chinese Han cohort. Moreover, it is important to note 19:231-234. that, by current study design, sequencing analysis was 9. Garber K: Neuroscience. Autism’s cause may reside in abnormalities at not conducted and we could have missed other rare the synapse. Science (New York, NY) 2007, 317:190-191. 10. Laumonnier F, Cuthbert PC, Grant SGN: The Role of Neuronal Complexes mutations potentially responsible for ASDs within these in Human X-Linked Brain Diseases. The American Journal of Human genes in our samples, such as those found in previous Genetics 2007, 80:205-220. studies or likely to be de novo. Additional screening of 11. 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Comoletti D, De Jaco A, Jennings LL, Flynn RE, Gaietta G, Tsigelny I, Acknowledgements Ellisman MH, Taylor P: The Arg451Cys-neuroligin-3 mutation associated We thank the subjects both of patients and controls and their families for with autism reveals a defect in protein processing. J Neurosci 2004, their support and participation. 24:4889-4893. 18. De Jaco A, Comoletti D, Kovarik Z, Gaietta G, Radic Z, Lockridge O, Author details Ellisman MH, Taylor P: A mutation linked with autism reveals a common Department of Pediatric Health Care, Children’s Hospital, Zhejiang University mechanism of endoplasmic reticulum retention for the alpha,beta- School of Medicine, Hangzhou, China. Department of Gastroenterology, hydrolase fold protein family. The Journal of biological chemistry 2006, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, 281:9667-9676. China. Department of Central Laboratory, Children’s Hospital, Zhejiang 19. 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