Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Neurodevelopmental Disorders
Published in: Journal of Neurodevelopmental Disorders 1/2014

Open Access 01-12-2014 | Research

Associations of HLA alleles with specific language impairment

Authors: Ron Nudel, Nuala H Simpson, Gillian Baird, Anne O’Hare, Gina Conti-Ramsden, Patrick F Bolton, Elizabeth R Hennessy, Anthony P Monaco, Julian C Knight, Bruce Winney, Simon E Fisher, Dianne F Newbury, The SLI Consortium

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2014

Login to get access

Abstract

Background

Human leukocyte antigen (HLA) loci have been implicated in several neurodevelopmental disorders in which language is affected. However, to date, no studies have investigated the possible involvement of HLA loci in specific language impairment (SLI), a disorder that is defined primarily upon unexpected language impairment. We report association analyses of single-nucleotide polymorphisms (SNPs) and HLA types in a cohort of individuals affected by language impairment.

Methods

We perform quantitative association analyses of three linguistic measures and case-control association analyses using both SNP data and imputed HLA types.

Results

Quantitative association analyses of imputed HLA types suggested a role for the HLA-A locus in susceptibility to SLI. HLA-A A1 was associated with a measure of short-term memory (P = 0.004) and A3 with expressive language ability (P = 0.006). Parent-of-origin effects were found between HLA-B B8 and HLA-DQA1*0501 and receptive language. These alleles have a negative correlation with receptive language ability when inherited from the mother (P = 0.021, P = 0.034, respectively) but are positively correlated with the same trait when paternally inherited (P = 0.013, P = 0.029, respectively). Finally, case control analyses using imputed HLA types indicated that the DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls (P = 0.004, relative risk = 2.575), as has been reported for individuals with attention deficit hyperactivity disorder (ADHD).

Conclusion

These preliminary data provide an intriguing link to those described by previous studies of other neurodevelopmental disorders and suggest a possible role for HLA loci in language disorders.
Appendix
Available only for authorised users
Literature
1.
Thomson G: A review of theoretical aspects of HLA and disease associations. Theor Popul Biol. 1981, 20: 168-208. 10.1016/0040-5809(81)90009-5.CrossRefPubMed
2.
Vandiedonck C, Knight JC: The human Major Histocompatibility Complex as a paradigm in genomics research. Brief Funct Genomic Proteomic. 2009, 8: 379-394. 10.1093/bfgp/elp010.PubMedCentralCrossRefPubMed
3.
Shiina T, Inoko H, Kulski JK: An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens. 2004, 64: 631-649. 10.1111/j.1399-0039.2004.00327.x.CrossRefPubMed
4.
Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, Vyse TJ, Rioux JD: Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008, 4: e1000024-10.1371/journal.pgen.1000024.PubMedCentralCrossRefPubMed
5.
6.
Wright P, Nimgaonkar VL, Donaldson PT, Murray RM: Schizophrenia and HLA: a review. Schizophr Res. 2001, 47: 1-12. 10.1016/S0920-9964(00)00022-0.CrossRefPubMed
7.
Torres AR, Sweeten TL, Cutler A, Bedke BJ, Fillmore M, Stubbs EG, Odell D: The association and linkage of the HLA-A2 class I allele with autism. Hum Immunol. 2006, 67: 346-351. 10.1016/j.humimm.2006.01.001.CrossRefPubMed
8.
Nevsimalova S, Tauberova A, Doutlik S, Kucera V, Dlouha O: A role of autoimmunity in the etiopathogenesis of Landau-Kleffner syndrome?. Brain Dev. 1992, 14: 342-345. 10.1016/S0387-7604(12)80157-4.CrossRefPubMed
9.
Connolly AM, Chez MG, Pestronk A, Arnold ST, Mehta S, Deuel RK: Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J Pediatr. 1999, 134: 607-613. 10.1016/S0022-3476(99)70248-9.CrossRefPubMed
10.
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A: Maternal neuronal antibodies associated with autism and a language disorder. Ann Neurol. 2003, 53: 533-537. 10.1002/ana.10557.CrossRefPubMed
11.
Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC: Quantitative trait locus for reading disability on chromosome 6. Science. 1994, 266: 276-279. 10.1126/science.7939663.CrossRefPubMed
12.
13.
Newbury DF, Bishop DV, Monaco AP: Genetic influences on language impairment and phonological short-term memory. Trends Cogn Sci. 2005, 9: 528-534. 10.1016/j.tics.2005.09.002.CrossRefPubMed
14.
The SLI Consortium: A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet. 2002, 70: 384-398. 10.1086/338649.PubMedCentralCrossRef
15.
Bartlett CW, Flax JF, Logue MW, Vieland VJ, Bassett AS, Tallal P, Brzustowicz LM: A major susceptibility locus for specific language impairment is located on 13q21. Am J Hum Genet. 2002, 71: 45-55. 10.1086/341095.PubMedCentralCrossRefPubMed
16.
Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, Groszer M, Alarcón M, Oliver PL, Davies KE, Geschwind DH, Monaco AP, Fisher SE: A functional genetic link between distinct developmental language disorders. N Engl J Med. 2008, 359: 2337-2345. 10.1056/NEJMoa0802828.PubMedCentralCrossRefPubMed
17.
Newbury DF, Winchester L, Addis L, Paracchini S, Buckingham LL, Clark A, Cohen W, Cowie H, Dworzynski K, Everitt A, Goodyer IM, Hennessy E, Kindley AD, Miller LL, Nasir J, O’Hare A, Shaw D, Simkin Z, Simonoff E, Slonims V, Watson J, Ragoussis J, Fisher SE, Seckl JR, Helms PJ, Bolton PF, Pickles A, Conti-Ramsden G, Baird G, Bishop DV, Monaco AP: CMIP and ATP2C2 modulate phonological short-term memory in language impairment. Am J Hum Genet. 2009, 85: 264-272. 10.1016/j.ajhg.2009.07.004.PubMedCentralCrossRefPubMed
18.
Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH: Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008, 82: 150-159. 10.1016/j.ajhg.2007.09.005.PubMedCentralCrossRefPubMed
19.
Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, D’arcy M, deBerardinis R, Frackelton E, Kim C, Lantieri F, Muganga BM, Wang L, Takeda T, Rappaport EF, Grant SF, Berrettini W, Devoto M, Shaikh TH, Hakonarson H, White PS: Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry. 2009, 15: 637-646.PubMedCentralCrossRefPubMed
20.
Poliak S, Peles E: The local differentiation of myelinated axons at nodes of Ranvier. Nat Rev Neurosci. 2003, 4: 968-980. 10.1038/nrn1253.CrossRefPubMed
21.
Kjelgaard MM, Tager-Flusberg H: An investigation of language impairment in autism: implications for genetic subgroups. Lang Cogn Process. 2001, 16: 287-308. 10.1080/01690960042000058.PubMedCentralCrossRefPubMed
22.
Bishop DVM: Autism and specific language impairment: categorical distinction or continuum?. Novartis Found Symp. 2003, 251: 213-226. Discussion 226-234, 281-297CrossRef
23.
Baird J, Stevenson JC, Williams DC: The evolution of ADHD: a disorder of communication?. Q Rev Biol. 2000, 75: 17-35. 10.1086/393256.CrossRefPubMed
24.
Redmond SM: Conversational profiles of children with ADHD, SLI and typical development. Clin Linguist Phon. 2004, 18: 107-125. 10.1080/02699200310001611612.CrossRefPubMed
25.
Whitehouse AJ, Barry JG, Bishop DVM: The broader language phenotype of autism: a comparison with specific language impairment. J Child Psychol Psychiatry. 2007, 48: 822-830. 10.1111/j.1469-7610.2007.01765.x.PubMedCentralCrossRefPubMed
26.
Bishop DVM, Baird G: Parent and teacher report of pragmatic aspects of communication: use of the children’s communication checklist in a clinical setting. Dev Med Child Neurol. 2001, 43: 809-818. 10.1017/S0012162201001475.CrossRefPubMed
27.
The SLI Consortium: Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet. 2004, 74: 1225-1238.CrossRef
28.
Monaco AP: Multivariate linkage analysis of specific language impairment (SLI). Ann Hum Genet. 2007, 71 (Pt 5): 660-673CrossRefPubMed
29.
Falcaro M, Pickles A, Newbury DF, Addis L, Banfield E, Fisher SE, Monaco AP, Simkin Z, Conti-Ramsden G: Genetic and phenotypic effects of phonological short-term memory and grammatical morphology in specific language impairment. Genes Brain Behav. 2008, 7: 393-402. 10.1111/j.1601-183X.2007.00364.x.CrossRefPubMed
30.
Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT: Data quality control in genetic case-control association studies. Nat Protoc. 2010, 5: 1564-1573. 10.1038/nprot.2010.116.PubMedCentralCrossRefPubMed
31.
Dilthey AT, Moutsianas L, Leslie S, McVean G: HLA*IMP-an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics. 2011, 27: 968-972. 10.1093/bioinformatics/btr061.PubMedCentralCrossRefPubMed
32.
Schreuder GM, Hurley CK, Marsh SG, Lau M, Maiers M, Kollman C, Noreen HJ: The HLA dictionary 2001: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol. 2001, 62: 826-849. 10.1016/S0198-8859(01)00271-3.CrossRefPubMed
33.
Palmer CG, Hsieh HJ, Reed EF, Lonnqvist J, Peltonen L, Woodward JA, Sinsheimer JS: HLA-B maternal-fetal genotype matching increases risk of schizophrenia. Am J Hum Genet. 2006, 79: 710-715. 10.1086/507829.PubMedCentralCrossRefPubMed
34.
Winney B, Boumertit A, Day T, Davison D, Echeta C, Evseeva I, Hutnik K, Leslie S, Nicodemus K, Royrvik EC, Tonks S, Yang X, Cheshire J, Longley P, Mateos P, Groom A, Relton C, Bishop DT, Black K, Northwood E, Parkinson L, Frayling TM, Steele A, Sampson JR, King T, Dixon R, Middleton D, Jennings B, Bowden R, Donnelly P, Bodmer W: People of the British Isles: preliminary analysis of genotypes and surnames in a UK-control population. Eur J Hum Genet. 2012, 20: 203-210. 10.1038/ejhg.2011.127.PubMedCentralCrossRefPubMed
35.
Semel EM, Wiig EH, Secord W: Clinical Evaluation of Language Fundamentals - Revised. 1992, San Antonio: Phychological Corporation
36.
Gathercole SE, Willis CS, Baddeley AD, Emslie H: The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory. 1994, 2: 103-127. 10.1080/09658219408258940.CrossRefPubMed
37.
Bishop DV, North T, Donlan C: Nonword repetition as a behavioural marker for inherited language impairment: evidence from a twin study. J Child Psychol Psychiatry. 1996, 37: 391-403. 10.1111/j.1469-7610.1996.tb01420.x.CrossRefPubMed
38.
Archibald LM, Joanisse MF: On the sensitivity and specificity of nonword repetition and sentence recall to language and memory impairments in children. J Speech Lang Hear Res. 2009, 52: 899-914. 10.1044/1092-4388(2009/08-0099).CrossRefPubMed
39.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002, 30: 97-101. 10.1038/ng786.CrossRefPubMed
40.
Abecasis GR, Cardon LR, Cookson WO: A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000, 66: 279-292. 10.1086/302698.PubMedCentralCrossRefPubMed
41.
Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC: Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet. 2012, 44: 502-510. 10.1038/ng.2205.PubMedCentralCrossRefPubMed
42.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007, 81: 559-575. 10.1086/519795.PubMedCentralCrossRefPubMed
43.
Carlson JM, Heckerman D, Shani G: Estimating false discovery rates for contingency tables. Microsoft Research technical report, MSR-TR-2009-53. 2009
44.
Morris JA, Gardner MJ: Calculating confidence intervals for relative risks (odds ratios) and standardised ratios and rates. Br Med J (Clin Res Ed). 1988, 296: 1313-1316. 10.1136/bmj.296.6632.1313.CrossRef
45.
Benjamini Y, Hochberg Y: Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995, 57: 289-300.
46.
Storey JD: A direct approach to false discovery rates. Journal of the Royal Statistical Society: Series B Statistical Methodology. 2002, 64: 479-498. 10.1111/1467-9868.00346.CrossRef
47.
Verhoeven KJF, Simonsen KL, McIntyre LM: Implementing false discovery rate control: increasing your power. Oikos. 2005, 108: 643-647. 10.1111/j.0030-1299.2005.13727.x.CrossRef
48.
Ramagopalan SV, Herrera BM, Bell JT, Dyment DA, Deluca GC, Lincoln MR, Orton SM, Chao MJ, Sadovnick AD, Ebers GC: Parental transmission of HLA-DRB1*15 in multiple sclerosis. Hum Genet. 2008, 122: 661-663. 10.1007/s00439-007-0442-z.CrossRefPubMed
49.
Wang Y-p, Tian Y, Zhu J-h, Yang Y-f, Zhang H-b, Wang C-h, Liu L, LV Y, Xiong L-p: Study on the association between HLA-DRB1 genes and ADHD in Xi’an. Chinese Journal of Child Health Care. 2008, 16: 010-
50.
Wright P, Donaldson PT, Underhill JA, Choudhuri K, Doherty DG, Murray RM: Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia. Am J Psychiatry. 1996, 153: 1530-1533.CrossRefPubMed
51.
Odell JD, Warren RP, Warren WL, Burger RA, Maciulis A: Association of genes within the major histocompatibility complex with attention deficit hyperactivity disorder. Neuropsychobiology. 1997, 35: 181-186. 10.1159/000119342.CrossRefPubMed
52.
Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D: The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum Immunol. 2002, 63: 311-316. 10.1016/S0198-8859(02)00374-9.CrossRefPubMed
53.
Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, Tyler JD, Zimmerman AW: HLA-DR4 in families with autism. Pediatr Neurol. 2006, 35: 303-307. 10.1016/j.pediatrneurol.2006.06.006.CrossRefPubMed
Metadata
Title
Associations of HLA alleles with specific language impairment
Authors
Ron Nudel
Nuala H Simpson
Gillian Baird
Anne O’Hare
Gina Conti-Ramsden
Patrick F Bolton
Elizabeth R Hennessy
Anthony P Monaco
Julian C Knight
Bruce Winney
Simon E Fisher
Dianne F Newbury
The SLI Consortium
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Neurodevelopmental Disorders / Issue 1/2014
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI
https://doi.org/10.1186/1866-1955-6-1

Other articles of this Issue 1/2014

Journal of Neurodevelopmental Disorders 1/2014 Go to the issue

Research

Copy number variation in Han Chinese individuals with autism spectrum disorder

Research

Pre-pulse inhibition and antisaccade performance indicate impaired attention modulation of cognitive inhibition in 22q11.2 deletion syndrome (22q11DS)

Research

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

Research

Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy (1H MRS)

Reviewer acknowledgement

Journal of Neurodevelopmental Disorders reviewer acknowledgement 2013

Research

Developmental delay in Rett syndrome: data from the natural history study