The WNT2 gene polymorphism associated with speech delay inherent to autism☆
Highlights
► We selectively investigated the role of a set of genes, FOXP2, WNT2, and EN2 on chromosome 7q, in language development in individuals with autism. ► Our exploratory study has provided suggestive evidence for the relationship between age of first phrase and the WNT2 gene. ► We detected a nominal effect of interaction between paternal age and rs2396753 in the FOXP2 gene on age of first phrase. ► The WNT2 gene and EN2 gene may act in concert to influence language development in autism.
Introduction
Autism is a severe developmental disorder characterized by heterogeneous clinical features, including impairments in language, behaviors, and social communication. The role of genetic factors in etiological pathways for autism has been extensively documented. Recently, genome-wide association studies have suggested a number of common genetic variants associated with the risk of autism (Anney et al., 2010, Ma et al., 2009, Wang et al., 2009), whereas many of these findings have not been confirmed in other populations yet. The failure to replicate the original positive finding in another population (a.k.a., “winner's curse”) may be partially attributed to genetic heterogeneity. Previous evidence indicates that the power of a meta-analysis to detect a small genetic effect decreases as between-study heterogeneity increases (Nakaoka & Inoue, 2009). Clinical heterogeneity has been found to be a norm rather than an exception in autism, and hence could lend some support to the presence of genetic heterogeneity. Several approaches to circumvent the problem of genetic heterogeneity include targeting clinically homogeneous populations and focusing on sub-phenotypes (Viding & Blakemore, 2007).
Speech delay is one of the hallmark features of autism. Previous family studies have suggested that language development is influenced by genetic factors (Lennon et al., 2007). For example, a review by Stromswold documents strong evidence for familial aggregation of disorders of speech and language (DSL); the prevalence of DSL in individuals of families of children diagnosed with DSL has been found to be 5–10 times higher than those without family history of DSL (Stromswold, 1998). DeThorne et al. (2006) reported that the heritability estimates for difficulties in expressive language and articulation were 0.54 and 0.97, respectively. Hence, these lines of evidence imply that genetic factors may play a larger role than environmental factors in the language development. Uncovering the genetic pathway associated with the language development related to autism may shed some light on the genetic basis of autism.
Previous studies have suggested that chromosome 7q may harbor genetic loci associated with language function. A genome-wide linkage study showed that age of first word in autism was linked to the 7q35-36 region (Alarcon, Cantor, Liu, Gilliam, & Geschwind, 2002). A follow-up linkage study incorporating “age of first word” by ordered subset analysis revealed that the linkage signal on 7q35-36 might be attributable to autistic individuals with an earlier onset of first word (Alarcon, Yonan, Gilliam, Cantor, & Geschwind, 2005). Another linkage study also confirmed that chromosome 7q may contain variants linked to language impairment (Villanueva et al., 2011). Meanwhile, Lai, Fisher, Hurst, Vargha-Khadem, and Monaco (2001) reported their landmark finding that mutations and translocation in the FOXP2 (forkhead box P2) gene (OMIM 605317) on chromosome 7q may cause verbal dyspraxia due to impaired motor sequences of orofacial muscles. A subsequent study showed that the mutations in the FOXP2 gene lead to impairments in not only sound production, but also written language and non-verbal cognitive functions (Watkins, Dronkers, & Vargha-Khadem, 2002). The FOXP2 gene encodes a transcription factor modulating expressions of a great many genes (Vernes et al., 2007). Among the genes regulated by the FOXP2 gene, the CNTNAP2 gene has been found to be related to nonsense-word repetition, an inheritable biomarker for specific language impairment (Vernes et al., 2008). In addition, a deletion in the WNT2 (wingless-type MMTV integration site family member 2) gene, located 2.2 Mb away from the FOXP2 gene on chromosome 7q, was found to be involved in specific language impairment (Lennon et al., 2007). Another 7q gene, the EN2 (Engrailed 2) gene, may also play a putative role in “presence of phrase speech” (Brune et al., 2008).
The associations between these candidate genes on 7q and risk of autism might be equivocal. Since these genes may play a role in language development, the inconsistent associations between loci and autism may be attributed to variation in language features. It has been proposed that incorporating speech-related endophenotypes may lead to the discovery of risk variants of heterogeneous effects of autism (Bradford et al., 2001). Hypothetically, these genes may contribute to the risk of autism by perturbing the language function. Alternatively, these loci may at best modulate language development in autism, while they play a limited role in susceptibility to autism. Hence, in the present study, we selectively investigated the role of a set of genes, FOXP2, WNT2 and EN2 on chromosome 7q, in language development in individuals with autism.
Section snippets
Subjects
The original sample consisted of totally 1164 subjects from 393 families (probands aged 9.1 ± 3.99 years, male 88.6%), recruited from the outpatient clinic of Psychiatric Department of three institutes (i.e., National Taiwan University Hospital and Chang-Gung Memorial Hospital, and Taoyuan Mental Hospital in Taoyuan) in Northern Taiwan. All subjects were Han Chinese. The initial diagnoses of probands were made by senior board-certified child psychiatrists based on the DSM-IV diagnostic criteria
Results
The demographic and clinical features of the 373 subjects diagnosed with autism were summarized in Table 1. The correlation matrix showed that age of first phrase was significantly correlated with verbal IQ and performance IQ, respectively (p < 0.001) (Table 2).
Significance of findings
Our exploratory study has suggested the link between age of first phrase and the WNT2 gene. The results do not lend strong support to the previously documented role of FOXP2 gene in language development. Nevertheless, to our knowledge, this is the first report of the association between the WNT2 gene and speech delay. These variants have been found to be associated with risk of autism in some (Gong et al., 2004, Marui et al., 2010, Wassink et al., 2001), but not all previous reports (Li et al.,
Conclusions
The current study has suggested that genetic variants in the WNT2 gene may play a role in the language development. These results are promising but demand replications for confirmations. The effect of the FOXP2 gene might be modified by paternal age, and hence other genetic/environmental factors related to paternal age might need to be explored to evaluate the role of the FOXP2 gene in language development. A better understanding of the biological process will pave the way for untangling its
Acknowledgements
This work was supported by grants from National Science Council (NSC96-3112-B-002-033; NSC97-3112-B-002-009; NSC98-3112-B-002-004), National Taiwan University Hospital (NTUH100-S1525; NTUH100-N1712) and National Health Research Institute, Taiwan.
References (43)
- et al.
Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families
American Journal of Human Genetics
(2002) Molecular genetics and animal models in autistic disorder
Brain Research Bulletin
(2002)- et al.
En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder
Brain Research
(2006) - et al.
No association of FOXP2 and PTPRZ1 on 7q31 with autism from the Japanese population
Neuroscience Research
(2005) - et al.
FOXP2 is not a major susceptibility gene for autism or specific language impairment
American Journal of Human Genetics
(2002) - et al.
PLINK: A tool set for whole-genome association and population-based linkage analyses
American Journal of Human Genetics
(2007) - et al.
Wnt2 regulates progenitor proliferation in the developing ventral midbrain
Journal of Biological Chemistry
(2010) - et al.
High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech and language disorders
American Journal of Human Genetics
(2007) - et al.
Mutation spectral changes in spermatogenic cells obtained from old mice
DNA Repair (Amsterdam)
(2004) - et al.
Quantitative genome scan and ordered-subsets analysis of autism endophenotypes support language QTLs
Molecular Psychiatry
(2005)
A genome-wide scan for common alleles affecting risk for autism
Human Molecular Genetics
Incorporating language phenotypes strengthens evidence of linkage to autism
American Journal of Medical Genetics
Heterogeneous association between engrailed-2 and autism in the CPEA network
American Journal of Medical Genetics B: Neuropsychiatric Genetics
Paternal age and autism are associated in a family-based sample
Molecular Psychiatry
On the parental origin of de novo mutation in man
Journal of Medical Genetics
Maternal and paternal age and risk of autism spectrum disorders
Archives of Pediatrics and Adolescent Medicine
Linguistic changes in verbal expression: A preclinical marker of Alzheimer's disease
Journal of International Neuropsychological Society
The ups and downs of Wnt signaling in prevalent neurological disorders
Oncogene
Children's history of speech-language difficulties: Genetic influences and associations with reading-related measures
Journal of Speech, Language, and Hearing Research
Behavioral problems and parenting style among Taiwanese children with autism and their siblings
Psychiatry and Clinical Neuroscience
Association between the FOXP2 gene and autistic disorder in Chinese population
American Journal of Medical Genetics B: Neuropsychiatric Genetics
Cited by (18)
Maternal exposure to prostaglandin E<inf>2</inf> modifies expression of Wnt genes in mouse brain – An autism connection
2018, Biochemistry and Biophysics ReportsCitation Excerpt :Two mutations of Wnt2 were found in two families with ASD [72], SNP mutations were detected in patients with autism [39], and strong associations were reported within a Chinese population of individuals with ASD [17]. A more recent study tested polymorphisms of the Wnt2 gene in individuals on the autism spectrum, and found that it may play a potential role in delayed speech [37]. Furthermore, we found that PGE2 significantly increased Wnt3a expression above the normal level in all developmental stages (E16, E19, and P8).
Planar Cell Polarity Gene Mutations in Autism Spectrum Disorder, Intellectual Disabilities, and Related Deletion/Duplication Syndromes
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual DisabilityConnecting signaling pathways underlying communication to ASD vulnerability
2013, International Review of NeurobiologyCitation Excerpt :This is extremely interesting given the dichotomous ratio (typically cited as 4:1) of male to female individuals identified with ASD (Werling & Geschwind, 2013). Many studies have investigated whether there is genetic variation in FOXP2 that is associated with ASD (Casey et al., 2012; Chien et al., 2011; Feuk et al., 2006; Gauthier et al., 2003; Gong et al., 2004; Laroche et al., 2008; Li, Yamagata, Mori, & Momoi, 2005; Lin et al., 2012; Marui et al., 2005; Newbury et al., 2002; O'Roak, Vives, Girirajan, et al., 2012; Richler, Reichert, Buxbaum, & McInnes, 2006; Toma et al., 2013; Wassink et al., 2002). The overall consensus of these studies is that there is scant evidence to support association between FOXP2 mutations and autism.
A translational exploration of the effects of WNT2 variants on altered cortical structures in autism spectrum disorder
2021, Journal of Psychiatry and NeuroscienceThree Decades of Valproate: A Current Model for Studying Autism Spectrum Disorder
2024, Current NeuropharmacologyRoles of Wnt Signaling Pathway and ROR2 Receptor in Embryonic Development: An Update Review Article
2022, Epigenetics Insights
- ☆
ClinicalTrials.gov number: NCT00494754.