Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry
© Sousa et al; licensee BioMed Central Ltd. 2010
Received: 2 September 2009
Accepted: 25 March 2010
Published: 25 March 2010
Autism spectrum disorders (ASDs) are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR) proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes - LRRTM1 (2p), LRRTM3 (10q), LRRN1 (3p) and LRRN3 (7q) - in order to identify common genetic risk factors underlying ASDs.
In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls.
Significant results were found for LRRN3 and LRRTM3 (P < 0.005), using both single locus and haplotype approaches. These results were further supported by a case-control analysis, which also highlighted additional SNPs in LRRTM3.
Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.
Autism is a genetically complex neurodevelopmental disorder, characterized by impairments in reciprocal social interaction and communication, along with restricted and stereotyped patterns of interests and behaviours . It is an extremely heterogeneous and highly heritable condition, affecting predominantly males (with an average sex ratio of 4:1), and with an onset before 3 years of age [2, 3]. Autism spectrum disorders (ASDs) refers to a broad definition of autism, including classical and atypical autism, Asperger syndrome and pervasive developmental disorder not otherwise specified . The aetiology of ASD is not fully understood and the causal variants and their modes of transmission remain elusive.
Leucine-rich repeats (LRRs) are common protein-protein interaction motifs and are typically 20-29 amino acids in length . LRR proteins are highly expressed in the nervous system and are involved in numerous biological functions, including nervous system development [5–10]. Mutations in LRR genes have been associated with different diseases, such as hereditary lateral temporal epilepsy  and Parkinson disease . Furthermore, a recent study suggested that LRR variants could possibly be involved in ASD susceptibility .
From the 313 known human LRR genes (NCBI Build 36.1), this work focused on four brain-enriched LRR candidates - LRRTM1, LRRTM3, LRRN1 and LRRN3. There are several LRR subfamilies, differentiated by the consensus sequence of the repeat and/or different combinations of supplementary domains [5, 8, 14]. One family of brain-enriched LRR containing type I transmembrane proteins is termed the LRRTM (leucine rich repeat transmembrane neuronal) family . This is a highly conserved four-member family which, with the exception of LRRTM4, has the unusual characteristic of being located in the introns of different α-catenin genes. Catenin family members are adhesion proteins that can form a complex with cadherins, which themselves have also been implicated in intellectual disability, autism and ASD risk [13, 15–17]. LRRTM messenger (m)RNAs are mainly expressed in the nervous system, each with a distinct and highly regulated pattern [8, 18]. It has recently been proposed that LRRTMs are synaptic organizing molecules and synaptogenic inducers in neurons, initiating excitatory presynaptic differentiation and mediating post-synaptic specializations . As several synaptic genes have been implicated in ASD, these genes become promising candidates to study .
LRRTM1 (MIM*610867), located on 2p12, lies within intron 7 of CTNNA2 (α2-catenin) with the highest mRNA expression in the brain and salivary gland . LRRTM1 is the first gene to be associated with both human handedness (relative hand skill) and schizophrenia  and is thought to be involved in brain development, neuronal connectivity, intracellular trafficking in axons and synaptogenesis [19, 21]. Therefore, it is an interesting candidate for autism where there is already some evidence for associations with abnormal asymmetrical brain structure in language-associated areas [22, 23].
Similarly, LRRTM3 (MIM*610869), on 10q22.1, is positioned within intron 7 of CTNNA3 (αT-catenin). This gene has a more restricted expression profile compared to LRRTM1, with expression in the brain, particularly the cerebellum [8, 24]. In addition, LRRTM3 is functionally and positionally linked to late-onset Alzheimer's disease [24, 25]. Moreover, CTNNA3 has also been recently suggested to be associated to ASD susceptibility .
The LRRN (leucine rich repeat neuronal) family of proteins has four known members in humans, all being brain-enriched type I transmembrane proteins . Studies in several species show that the members of this family have different spatial and temporal expression patterns and that they are involved in neural development and regeneration [14, 27–29]. Although they seem to function as adhesion molecules or binding receptors in regulatory mechanisms, their biological activities and specific central nervous system (CNS) functions in humans are still unclear [30, 31].
LRRN1, located on 3p26.2, is again a nested gene located in intron 8 of the long form of SUMF1 (sulphatase modifying factor 1) (NM_182760). In the developing neural cells of the chick, Lrrn1 is localized in the endosome, suggesting that it might be involved in the regulation of cell adhesion and signalling pathways . LRRN1 shows a high degree of sequence conservation and comparison to its expression in the mouse indicates that it is dynamically expressed in the somites and the neural plate during development, and mostly in the brain and kidney in the adult . Furthermore, LRRN1 is located within a candidate region for recessive non-syndromic mental retardation on chromosome 3 . Additionally, a paternally inherited duplication (3p26.1-26.2) which encompasses LRRN1 was reported in children with autism and additional developmental abnormalities .
Finally, LRRN3 maps to 7q31.1 and is brain-enriched [14, 31, 35]. LRRN3 is a nested gene in IMMP2L (inner mitochondrial membrane peptidase-like), being positioned within intron 3. The molecular structure and expression pattern of Lrrn3, suggest that it plays a role in the development and maintenance of the nervous system . Other studies have shown that Lrrn3 exhibits regulated expression in the developing ganglia and motor neurons of the neural system, and is upregulated during neuronal cortical injury [14, 27, 28]. In addition, one of the most consistently replicated loci for autism, first identified by The International Molecular Genetic Study of Autism Consortium (IMGSAC) , is on 7q21.3-7q34 [37–43]. As LRRN3 is located under the linkage peak of interest for IMGSAC families, and there is evidence of an association with the IMMP2L/DOCK4 region in the IMGSAC cohort , we considered LRRN3 to be an appealing candidate for ASD susceptibility, despite a previous study failing to find evidence of an association between this gene and autism in their cohorts .
Here, the roles of LRRTM1, LRRTM3, LRRN1 and LRRN3 in ASD susceptibility were studied in four different populations of European ancestry (IMGSAC, Italian, German and Northern Dutch). The variation at these four loci was assessed and the association of gene variants and haplotypes with ASD was tested in a family based study. Significant evidence of their association to ASD was found for LRRN3 and LRRTM3. In order to complement this analysis, a case-control study was performed, partially supporting the evidence of association found in LRRN3 and LRRTM3. To our knowledge, this is one of the most comprehensive genetic analyses of association between these genes and ASD risk.
All the individuals who participated in this study are Caucasian and of European ancestry. Four cohorts were used, our core IMGSAC set consisting mainly of UK families, two groups from Italy and Germany (collected as part of the IMGSAC collaboration) and a population from the north of the Netherlands. These cohorts are referred to as IMGSAC, Italian, German and Northern Dutch, respectively. A total of 2758 individuals from 661 families [439 IMGSAC (350 multiplex and 89 singleton), 85 Italian, 30 German and 107 Northern Dutch] were analysed. The male:female ratio of the affected individuals is 4.1:1. Also, a cohort of 295 UK DNA controls [European Collection of Cell Cultures (ECACC]) was used for the case-control study. ECACC controls were randomly selected, non-related, UK Caucasian blood donors http://www.hpacultures.org.uk/products/dna/hrcdna/hrcdna.jsp. For the IMGSAC sample collection the identification of families, assessment methods and inclusion criteria used have been described previously . Briefly, after identification in an initial screen for autism, parents undertook the Autism Diagnostic Interview-Revised (ADI-R)  and the Vineland Adaptive Behaviour Scales . Probands were assessed using the Autism Diagnostic Observation Schedule (ADOS)  and a clinical evaluation was undertaken in order to exclude known medical disorders aetiologically associated with autism (for example, tuberous sclerosis and neurofibromatosis). Karyotypes were obtained for probands when possible and molecular genetic testing for fragile X syndrome carried out on one affected case per family. A blood sample was taken from both probands and available first degree relatives. DNA was extracted from blood samples, buccal swabs or cell lines using a DNA purification kit (Nucleon® BACC2 Blood and Cell Culture DNA purification kit, Tepnel Life Sciences, Manchester, UK) and standard techniques. The Italian and German populations had the same assessment as that described above as they are part of the wider IMGSAC group. For the Northern Dutch population the subjects and their assessment are again described in detail elsewhere . In short, the families were recruited through an epidemiological survey and an autism outpatient clinic affiliated with the Child and Adolescent Psychiatry Center of Groningen. The diagnosis criteria were very similar to those previously described for IMGSAC (including ADI-R and ADOS assessments) and the children's intellectual functioning was evaluated as described by Mulder et al. . DNA was extracted from cheek cells obtained by mouth swabs from patients, parents and siblings using the Epicentre MasterAmp™ DNA Extraction Solution Kit (BiozymTC, Landgraaf, the Netherlands). The study was reviewed by the relevant ethical committees. For IMGSAC population cohort the ethical approval was carried out by:
(a) Europe (UK - Oxfordshire Psychiatric Research Ethics Committee A, under the review number O03.013 and title name 'Identifying and understanding the actions of autism susceptibility genes'; Cambridge Local Research Ethics Committee; Institute of Psychiatry Ethical Research Committee; Joint Ethics Committee (Newcastle & North Tyneside Health Authority/Universities of Newcastle upon Tyne/Northumbria); Salford and Trafford Research Ethics Committee/Denmark - Den Videnskabsetiske Komite, Kobenhavns Amt/Finland - Ethical Committee for the Hospital of Children and Adolescents and Psychiatry (University Central Hospital)/France - Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale Groupe Hospitalier Pitié-Salpêtrière-Paris/Germany - Ethik-Kommission des Fachbereichs Medizin der Johann Wolfgang Goethe (Universität Frankfurt am Main); Heidelberg Ethikkommission der Medizinischen Fakultät/Greece - Agia Sophia Hospital Ethics Committee/Italy - Comitato Etico IRCCS Fondazione Stella Maris/Netherlands - Medisch Ethische Toetsingscommissie/Sweden - Ethical Review Board of Sahlgren's Academy, Goteborg University Faculty of Medicine
(b) USA - Yale University School of Medicine Human Investigation Committee; University of Illinois at Chicago's Office for the Protection of Research Subjects; University of Michigan Medical School IRBMED
(c) Canada - The Hospital for Sick Children, Research Ethics Board; Hamilton Health Sciences/McMaster University Research Ethics Board.
For the Northern Dutch population cohort, ethical review was done by the Medical Ethical Committee of the University Medical Center Groningen under review number M08.057360.
Written informed consent was provided by all parents/guardians and, when possible, by the affected individuals. The IMGSAC cases are Caucasian, but from different sites in Europe and the USA. Therefore, population substructure is a distinct possibility. The samples used for the current study have substantial overlap with the IMGSAC samples described in Maestrini et al. , where no evidence of strong population stratification was detected. However, it is possible that subtle or low levels of population stratification may be present, potentially leading to false positives in the case-control analysis.
Single nucleotide polymorphism (SNP) selection
Genotyping data from Centre d'Etude du Polymorphisme Humain individuals was downloaded from the HapMap phase II (release 24) for each gene and approximately 5 kb of upstream and downstream sequence. This resulted in information for the four following regions being obtained: 2p12 (80381256-80386255); 10q22.1 (68353045-68532626); 3p26.2 (3814162-3866687); and 7q31.1 (110516705-110554408). Sixty-seven haplotype tagging SNPs were chosen across these loci using Tagger from Haploview v4.0  [r2 > 0.8 and minor allele frequency (MAF) > 0.05, aggressive tagging], capturing the maximum amount of genetic variation in the four regions. In addition, one 3'untranslated region and two synonymous SNPs in LRRTM1 were genotyped, as these were the only markers left to genotype in order to complete the whole coverage of this region.
The genotyping assay was designed using the MassARRAY software (Sequenom) and genotypes obtained using the MassARRAYTyper™ system (version 188.8.131.52). Quantification of DNA samples was performed using the Picogreen®dsDNA Quantitation Kit (Invitrogen, Oregon, USA) and 40 ng of genomic DNA per sample was used in the genotyping assay. Genotyping was performed using the Sequenom MALDI-TOF iPLEX platform (Sequenom, San Diego, USA). The sample and marker genotyping success rates were ~98% and 94%, respectively. Based on two control samples included on each plate as genotyping controls, we found high inter-plate reproducibility (99.8%). Genotype Analyzer (Sequenom) was used to visually check the quality of each genotype call, assigning alleles where possible. An in-house database  was used to store all genotypic data and to produce files for statistical analysis.
Genotypes were checked for Mendelian consistency using PedCheck  and any inconsistent genotypes were removed. Genotypes flanking double recombinants were detected using MERLIN  and, in ambiguous cases where probable excess recombination occurred, genotypes were reconfirmed and corrected as necessary. All the SNPs were tested for Hardy-Weinberg equilibrium using a χ2 test, in parents and probands separately.
Multiple testing correction
Performing multiple statistical tests leads to inflation in the occurrence of false positives and it is therefore necessary to adjust the statistical significance (P-value) threshold (usually 5%) in order to account for the number of independent tests. A Bonferroni correction using the total number of SNPs would be too conservative because of the high LD between SNPs in the analysed regions . By considering the LD pattern, which identified 10 independent haplotype blocks, it is reasonable to interpret using a P < 0.005 (= 0.05/10) to be statistically significant. Using a separate permutation approach we found a similar (5%) significance threshold (P < 0.0048) based on inference of the maximum chi-square statistic observed over all genotyped SNPs. In particular, both the transmitted/untransmitted and case-control status of the chromosomes were randomly permuted 10,000 times. From each of the 10,000 random experiments, in both trio and case-control studies, we determined the maximum chi-square statistics over all SNPs genotyped. We ordered these statistics and then calculated the 95 percentile. This was the estimate of the 0.05 significance level for the experiment performed, assuming inference is taken with respect to maximum chi-square statistic observed over all genotyped SNPs.
Haplotype transmission disequilibrium results in the overall population across leucine-rich repeat transmembrane neuronal (LRRTM3).
Block 2 (rs716546-rs716547-rs9971243)
Block 2 (rs716546-rs716547-rs9971243)
rs6480245, rs12266823 b
rs6480245, rs12266823 b
Haplotype transmission disequilibrium results per population across the four genes studied.
Block 2 (rs10261004-rs214884)
0.35 (0.16, 0.74)
Block 2 (rs10261004-rs214884)
2.20 (1.30, 3.73)
Block 3 (rs10510278-rs696489)
1.40 (1.03, 1.90)
Block 3 (rs10510278-rs696489)
0.72 (0.52, 1.00)
rs10780025, rs13100776 b
0.49 (0.28, 0.85)
rs1925613, rs10762138 b
0.40 (0.18, 0.91)
rs1925613, rs1925624 b
1.36 (1.06, 1.76)
rs2619652, rs12785206 b
2.57 (1.07, 6.16)
rs2619652, rs12785206 b
0.41 (0.19, 0.89)
rs1925613, rs12785206 b
0.38 (0.17, 0.86)
Case-control genotype-based test results.
TT versus GG/GT
AG versus GG/AA
AA versus GG/AG
AA versus GG/AG
CC versus AA/AC
CC versus AA/AC
GG versus AA/AG
GG versus AA/AG
TT versus CC/CT
TT versus CC/CT
TT versus CC/CT
TT versus CC/CT
CC/CT versus TT
Recently, there has been increasing attention towards the LRR group of transmembrane proteins and their relationship with neurological complex disorders. The LRRs analysed here are thought to be synaptic organizing molecules and have been implicated in brain development, which is often impaired in autistic individuals [8, 14, 18, 19, 21, 32]. In the current study, we hypothesized that common variants in the leucine motifs gene class could possibly be involved in ASD pathogenesis. Specifically, LRRTM1, LRRTM3, LRRN1 and LRRN3 were examined as candidate genes in four different populations of European ancestry by carrying out parallel family-based and case-control studies.
LRRN1 showed only one significant result with the marker rs1488454, showing that its C allele is increasing the susceptibility to ASDs in the singleton cohort. However, this result was not confirmed by the case-control analysis which points to a weaker evidence for a role in susceptibility.
The family based study showed that rs10261004 within LRRN3 is strongly associated with ASD risk in the Northern Dutch cohort and that its G allele is protective for susceptibility to the disorder. The haplotype analysis also showed evidence of significance with two haplotypes within LD block 2. Moreover, the case-control analysis confirmed the evidence of an association with this marker, showing a decreased risk for the G allele and for the GG/GT genotypes (compared to the T allele and TT genotype, respectively). This is the most consistent result that we have found, as the marker is significant in all the tests performed in the Northern Dutch cohort and, therefore, it could be a population specific susceptibility. The non-association reported for this gene in the Collaborative Linkage Study of Autism dataset by Hutcheson et al.  could be explained by several factors: differences in sample ascertainment, family numbers and the hypothesis that one of the results is a false positive. In effect, they tested 30 nuclear families, which could have limited their ability to detect the association signal that we are observing in our cohort. In addition, none of the four markers tested in their study were in high LD with rs10261004.
LRRTM3 was the gene that showed most evidence of association in the populations that we studied. In particular, rs1998753 was the most consistent significant marker within this gene, showing that its G allele increases the risk for ASD, especially in the multiplex cohort (but was also significant in the pooled meta-analysis). Although this effect was evident in all case-control cohorts except the Northern Dutch, it did not reach a significant level of statistical evidence. In fact, in the Northern Dutch case-control cohort, which is a more isolated population than the others, there is strong evidence that the A allele increases the risk for ASD and that there is a non-significant over-transmission of the A allele to cases in the TDT. Consequently, for the case-control, although the Northern Dutch result could be a false positive, it biases the overall results. The statistical power of the case-control analysis is hindered by the small sample size of our control cohort, by sampling cases from a population possibly different to the others and by false positives which were possibly due to the population structure. In contrast, the family-based study is robust to population stratification. So, although the case-control result can be taken as a verification of the positive evidence of association with this marker, this result warrants further confirmation that could be achieved by another replication study or by genotyping a larger control group for this marker, preferably including a set of controls from the Northern Dutch population. In addition to rs1998753, rs12266823 was also significant, with the A allele being protective against ASD risk in the multiplex cohort and in the pooled meta-analysis of the TDT. However, this result was not confirmed by the case-control analysis. Nevertheless, new associations within LRRTM3 were found in the case-control study with the markers rs17279006, rs1925613, rs10997482, rs2619652, rs10740268 and rs12785206. All of these were significant in the overall analysis. For rs17279006 the G allele and GG(/GT) genotypes were protective against the disorder, whereas for the rs1925613 C allele, and CC(/CA) and rs10997482 G allele and GG(/GA) genotypes, the risk of ASD was increased (the last two markers being most significant in the singleton cohort in the genotypic test). For rs10740268 the C allele and CC(/CT) genotypes there was an increasing risk to ASDs in the overall meta-analysis. Moreover, rs2619652 and rs12785206 were both significant in the singleton cohort; the first presenting an increased risk for the C allele and CC (/CT) genotypes and the second having a decreased risk for the C allele and CC/CT genotypes. Therefore, overall there is growing evidence that LRRTM3 may play a role in ASD susceptibility.
Interestingly, significant results from the TDT analysis were only replicated in the case-control study for two markers. However, seven new significant markers appeared in the latter that were not previously identified by the TDT. Several explanations can be proposed for this occurrence but the most evident is the use of different analytical approaches. Both TDT and case-control studies use different methods to access association, and while the TDT is more robust to population stratification, the case-control has in general more power to detect association in studies such as ours. We cannot exclude the possibility that subtle population structure (detected using many hundreds or thousands of markers) may lead to false positive results in the case-control analyses above. We suggest further that there should be an assessment of the case-control specific association markers in a larger number of controls and, if possible, a correction for population structure or other confounding effects using many more markers. The two analyses presented complement each other and reflect the complex heterogeneity of the disorder spectrum, pointing once more to the difficulty of studying ASDs. Additionally, different markers within LRRTM3 were differently associated to multiplex and singleton families, supporting the theory that we are looking at genetically different groups within the same population that have different patterns of ASD traits [59, 60].
As both associated genes, LRRTM3 and LRRN3, are nested, they are possibly transcriptionally co-regulated with the genes that contain them (CTNNA3 and IMMP2L, respectively) . Unknown regulatory mechanisms could be present in these regions altering gene expression or even splicing patterns which, in turn, could contribute to ASD susceptibility. Moreover, Wang et al. found an association with autism with one intronic marker (rs9651325) in CTNNA3, which is located 3' to LRRTM3, a region that was not covered by our study . Both these LRR genes warrant further investigation as they are highly expressed in the brain, particularly the cerebellum, [8, 14] (a characteristically impaired region in autistic individuals [62, 63]), involved in central nervous system development and regeneration [8, 14, 27, 28, 31], and there is accumulating evidence implicating these genic regions in ASD susceptibility [13, 44].
Taken together, there is converging evidence that common genetic variants in LRRTM3 and LRRN3 confer susceptibility to ASD and further study of these genes and their function will provide valuable insights into their role in ASD pathogenesis. In summary, this is one of the first studies to show results of an association between more than one leucine-rich repeat gene and ASD susceptibility in populations of European ancestry.
List of Abbreviations
autism spectrum disorders
autism diagnostic interview-revised
autism diagnostic observation schedule
central nervous system
The International Molecular Genetic Study of Autism Consortium
- IMMP2L :
inner mitochondrial membrane peptidase-like
leucine rich repeat neuronal
leucine rich repeat transmembrane neuronal
minor allele frequency
single nucleotide polymorphism
transmission disequilibrium test.
We sincerely thank all the families who have participated in the study and the professionals who made this study possible. We would like to thank Chris Allan at the WTCHG core genomics facility for technical support (Sequenom genotyping). We gratefully thank Nuala Sykes, Kirsty Wing, Clotilde Leveque and Susana Campino for their helpful discussions and critical comments. This work was supported by the Nancy Lurie Marks Family Foundation; the Simons Foundation; the EC 6th FP AUTISM MOLGEN [grant No. LSHM-CT-2005-512158]; the Wellcome Trust [grant No. 076566/Z/05/Z]; and the Fundação para a Ciência e Tecnologia (FCT-Portugal). IS is funded by FCT-Portugal (SFRH/BD/21405/2005). TGC is funded by the Bill and Melinda Gates Foundation through the National Institutes of Health [grant No. 566], the Wellcome Trust [grant No. 077383/Z/05/Z] and the Medical Research Council UK [grant No. G0600230]. RH and AB are funded by the EC 6th FP AUTISM MOLGEN [grant No. LSHM-CT-2005-512158]; ATP is funded by the Nancy Lurie Marks Family Foundation and the Simons Foundation; EM and RBM are funded through the EC 6th FP AUTISM MOLGEN [grant No. LSHM-CT-2005-512158], the Accare (University Center Child and Adolescent Psychiatry) and through the Netherlands Organization for Scientific Research (NWO). SMK and FP are funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) grant No. PO 255/17-4; APM is funded by the Nancy Lurie Marks Family Foundation and the Simons Foundation.
International Molecular Genetic Study of Autism Consortium (IMGSAC): http://www.well.ox.ac.uk/monaco/autism/IMGSAC.shtml
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