Autism

Autism is a behaviourally defined neurodevelopmental disorder characterised by impairments in verbal and non-verbal communication, social interaction, and repetitive and stereotyped behaviours, and is often associated with mental retardation and epilepsy. The symptoms of autism change with development, and the behavioural spectrum is highly variable extending to other qualitatively similar autism spectrum disorders, and related but milder behavioural abnormalities in some relatives. Autism Spectrum Disorders include Asperger syndrome, Rett syndrome, pervasive developmental disorder - not otherwise specified (PDD-NOS), and childhood disintegrative disorder. Recent prevalence estimates suggest that childhood autism affects approximately 4 in 1000 people, with autism spectrum disorders affecting over 1 in 100, and with a male to female ratio of 4:1. There is substantial evidence for the involvement of several genetic factors in susceptibility to autism. However, despite this high prevalence, the cause(s) of autism are still unknown in many cases, presenting a considerable clinical challenge. There is no widely effective treatment and ASDs impact on individuals, their families and society more broadly.

Aims of our research

Our research aims to identify genetic variants increasing risk of autism, in order to improve understanding of the biological pathways underlying autism. Ultimately, this may identify potential biomarkers or indicate targets for improved intervention and treatment strategies.

Research projects

Previous research has been carried out in collaboration with two large international consortia; the International Molecular Genetic Study of Autism Consortium (IMGSAC), and the Autism Genome Project (AGP). Through these consortia, we have used state-of-the-art technologies to analyse hundreds of thousands of genetic variants across the entire human genome in over one thousand families with children affected by autism using genomewide association study and copy number variation approaches.

This research has led to the discovery of several rare intragenic mutations and submicroscopic insertions or deletions (copy number variants) that appear to increase the risk of autism. These findings are beginning to shed light on the underlying biological pathways and mechanisms, pointing to the involvement of defective glutamatergic synaptogenesis, neuronal cell adhesion and postsynaptic density genes in susceptibility to autism. Some of these variants are also implicated in mental retardation and other neurodevelopmental and psychiatric disorders. These observations have led to increasing recognition of the presence of considerable genetic and clinical heterogeneity underlying autism spectrum disorders, with the likely contribution of both common and rare variation in multiple genes with diverse functions.

In an ongoing research project, we are using deep sequencing and computational biology approaches to investigate the involvement of microRNAs in the development of autism. MicroRNAs are small non-protein coding genes, which have a role in a diverse range of cellular processes through regulating the amount of protein produced from a large number of genes. The involvement of microRNAs in several psychiatric and neurological disorders has been recently suggested, indicating that microRNAs may contribute to the clinical heterogeneity of autism.

People and collaborators

Dr Janine Lamb

Research is being carried out in collaboration with two large international consortia; the International Molecular Genetic Study of Autism Consortium (IMGSAC), and the Autism Genome Project (AGP), and colleagues from within the Faculty of Medical and Human Sciences and Faculty of Life Sciences.

This research is being carried out as part of a broader framework of paediatric and adult autism research using a variety of approaches at the University of Manchester. This includes a number of academics from the Institutes of Human Development, Brain, Behaviour and Mental Health, and School of Psychological Sciences (Faculty of Medical and Human Sciences), the Faculty of Life Sciences, the Biomedical Imaging Institute and the Neuroscience Research Institute.

Publications

2012

  • Anney, et al (2012). Individual common variants exert weak effects on the risk for autism spectrum disorders. Hum Mol Genet, eScholarID:178443 | PMID:22843504 | DOI:10.1093/hmg/dds301
  • Casey, et al (2012). A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet, 131(4), 565-79. eScholarID:158924 | PMID:21996756 | DOI:10.1007/s00439-011-1094-6
  • Gregersen, P., Kosoy, R., Lee, A., Lamb, J., Sussman, J., McKee, D., Simpfendorfer, K., Pirskanen-Matell, R., Piehl, F., Pan-Hammarstrom, Q., Verschuuren, J., Titulaer, M., Niks, E., Marx, A., Strubel, P., Tackenberg, B., Patz, M., Maniaol, A., Elsais, A., Tallaksen, C., Harbo, H., Lie, B., Raychaudhuri, S., de Bakker, P., Melms, A., Garchon, H., Willcox, N., Hammarstrom, L. & Seldin, M (2012). Risk for myasthenia gravis maps to a (151) Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol, eScholarID:178442 | PMID:23055271 | DOI:10.1002/ana.23691

2011

  • Lamb, J.A. (2011). Whole Genome Linkage and Association Analyses. In Amaral, D., Dawson, G., Geschwind, D (Ed.), Autism Spectrum Disorders. Oxford, UK: Oxford University Press. eScholarID:108153
  • Anney, et al (2011). Gene-ontology enrichment analysis in two independent family-based samples highlights biologically plausible processes for autism spectrum disorders. Eur J Hum Genet, Epub ahead of print, eScholarID:125811 | PMID:21522181 | DOI:10.1038/ejhg.2011.75
  • Chinoy, H., Lamb, J., Ollier, W. & Cooper, R (2011). Recent advances in the immunogenetics of idiopathic inflammatory myopathy. Arthritis Res Ther, 13(3), 216 (Epub ahead of print). eScholarID:125810 | PMID:21658295 | DOI:10.1186/ar3327
  • Chinoy, H., Lamb, J.A., Ollier, W.E.R., Cooper, R.G. (In-press). The Genetics of Myositis. Arthritis Research and Therapy, eScholarID:108151

2010

  • Autism et al. (2010). A genomewide scan for common alleles affecting risk for autism. Human Molecular Genetics, 19(20), 4072-4082. eScholarID:108121 | DOI:10.1093/hmg/ddq307
  • Pinto, et al (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466(7304), 368-372. eScholarID:82891 | PMID:20531469 | DOI:10.1038/nature09146

2009

  • Asher J, Lamb J, Brocklebank D, Cazier J, Maestrini E, Addis L, Sen M, Baron-Cohen S, Monaco A. (2009). A whole-genome scan and fine-mapping linkage study of auditory-visual synesthesia reveals evidence of linkage to chromosomes 2q24, 5q33, 6p12, and 12p12. Am J Hum Genet, 84(2), 279-285. eScholarID:1d18818 | DOI:10.1016/j.ajhg.2009.01.012
  • Chinoy, H., Lamb, J., Ollier, W. & Cooper, R (2009). An update on the immunogenetics of idiopathic inflammatory myopathies: major histocompatibility complex and beyond. Curr Opin Rheumatol, 21(6), 588-593. eScholarID:68198 | PMID:19730377 | DOI:10.1097/BOR.0b013e3283315a22
  • Lamb, J.A. (2009). Molecular Genetics of Autism. Encyclopedia of Life Sciences (ELS), EPub, eScholarID:54252 | DOI:10.1002/9780470015902.a0021455
  • Maestrini, E, Pagnamenta, A, Lamb, J, Bacchelli, E, Sykes, N, Sousa, I, Toma, C, Barnby, G, Butler, H, Winchester, L, Scerri, T, Minopoli, F, Reichert, J, Cai, G, Buxbaum, J, Korvatska, O, Schellenberg, G, Dawson, G, Bildt, A, Minderaa, R, Mulder, E, Morris, A, Bailey, A, Monaco, A. (2009). High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol Psychiatry, Epub ahead of print, eScholarID:1d20694 | DOI:10.1038/mp.2009.34
  • Newbury, D, Warburton, P, Wilson, N, Bacchelli, E, Carone, S, Lamb, J, Maestrini, E, Volpi, E, Mohammed, S, Baird, G, Monaco, A. (2009). Mapping of partially overlapping de novo deletions across an autism susceptibility region (AUTS5) in two unrelated individuals affected by developmental delays with communication impairment. Am J Med Genet A, 149(4), 588-597. eScholarID:1d18817 | DOI:10.1002/ajmg.a.32704
  • Pagnamenta, A, Wing, K, Akha, E, Knight, S, Bolte, S, Schmotzer, G, Duketis, E, Poustka, F, Klauck, S, Poustka, A, Ragoussis, J, Bailey, A, Monaco, A, Lamb, J, International Molecular Genetic Study of Autism Consortium (IMGSAC). (2009). A 15q13.3 microdeletion segregating with autism. Eur J Hum Genet, 17(5), 687-692. eScholarID:1d20696 | DOI:10.1038/ejhg.2008.228
  • Sykes, N., Toma, C., Wilson, N., Volpi, E., Sousa, I., Pagnamenta, A., Tancredi, R., Battaglia, A., Maestrini, E., Bailey, A., Monaco, A. & IMGSAC, I (2009). Copy number variation and association analysis of SHANK3 as a candidate gene for autism in the IMGSAC collection. Eur J Hum Genet, 17(10), 1347-53. eScholarID:54366 | PMID:19384346 | DOI:10.1038/ejhg.2009.47
  • Weiss, L., Arking, D., , T., Daly, M. & Chakravarti, A (2009). A genome-wide linkage and association scan reveals novel loci for autism. Nature, 461(7265), 802-8. eScholarID:83363 | PMID:19812673 | DOI:10.1038/nature08490

2008

  • Autism Genome Project Consortium, Liu X, Paterson A, Szatmari P, Lamb J. (2008). Genome-wide linkage analyses of quantitative and categorical autism subphenotypes. Biol Psychiatry, 64(7), 561-570. eScholarID:1d18848 | DOI:10.1016/j.biopsych.2008.05.023
  • BrownJ.J, Ollier WER, ArscottG, Ke X, Lamb J, Day PJR, BayatA. (2008). Genetic susceptibility to Keloid scarring: SMAD gene SNP frequencies in Afro-Caribbeans. Exp. Dermatol, 17(7), 610-613. eScholarID:1d17650 | DOI:10.1111/j.1600-0625.2007.00654.x
  • Chinoy, H, Platt, H, Lamb, J, Betteridge, Z, Gunawardena, H, Fertig, N, Varsani, H, Davidson, J, Oddis, C, McHugh, N, Wedderburn, L, Ollier, WER, Cooper, RG, NULL. (2008). The protein tyrosine phosphatase N22 gene is associated with juvenile and adult idiopathic inflammatory myopathy independent of the HLA 8.1 haplotype in British Caucasian patients. Arthritis Rheum, 58(10), 3247-3254. eScholarID:1d17861 | DOI:10.1002/art.23900
  • Gong, X., Bacchelli, E., Blasi, F., Toma, C., Betancur, C., Chaste, P., Delorme, R., Durand, C., Fauchereau, F., Botros, H., Leboyer, M., Mouren-Simeoni, M., Nygren, G., Anckarsater, H., Rastam, M., Gillberg, I., Gillberg, C., Moreno-De-Luca, D., Carone, S., Nummela, I., Rossi, M., Battaglia, A., IMGSAC, I., Jarvela, I., Maestrini, E. & Bourgeron, T (2008). Analysis of X chromosome inactivation in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet, 147B(6), 830-5. eScholarID:54338 | PMID:18361425 | DOI:10.1002/ajmg.b.30688
  • Sousa, I, Clark, T, Toma, C, Kobayashi, K, Choma, M, Holt, R, Sykes, N, Lamb, J, Bailey, A, Battaglia, A, Maestrini, E, Monaco, A. (2008). MET and autism susceptibility: family and case-control studies. Eur J Hum Genet, 17(6), 749-758. eScholarID:1d18819 | DOI:10.1038/ejhg.2008.215

2007

  • Autism et al. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet, 39(3), 319-328. eScholarID:1d17169 | DOI:10.1038/ng1985
  • Sykes, N.H and Lamb, J.A. (2007). Autism: the quest for the genes. Expert Rev Mol Med, 9(24), 1-15. eScholarID:58301 | DOI:10.1017/S1462399407000452
  • Toma, C., Rossi, M., Sousa, I., Blasi, F., Bacchelli, E., Alen, R., Vanhala, R., Monaco, A.P., Jarvela, I., Maestrini, E., International Molecular Genetic Study of Autism Consortium (IMGSAC). (2007). Is ASMT a susceptibility gene for Autism Spectrum Disorders? A replication study in European populations. Molecular Psychiatry, 12(11), 977-979. eScholarID:58369 | DOI:10.1038/sj.mp.4002069

2006

  • Bonora, E., Lamb, J.A., Barnby, G. Bailey, A.J., and Monaco, A.P. (2006). Genetic Basis of Autism. In Moldin, S.O. and Rubenstein, J.L.R (Ed.), Understanding Autism: From Basic Neuroscience to Treatment. (pp. 49-74). CRC Press. eScholarID:58151
  • Blasi, F., Bacchelli, E., Carone, S., Toma, C., Monaco, A., Bailey, A., Maestrini, E. & IMGSAC, I (2006). SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample. Eur J Hum Genet, 14(1), 123-6. eScholarID:54340 | PMID:16205742 | DOI:10.1038/sj.ejhg.5201444
  • Blasi, F., Bacchelli, E., Pesaresi, G., Carone, S., Bailey, A., Maestrini, E. & IMGSAC, I (2006). Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet, 141B(3), 220-1. eScholarID:54339 | PMID:16508939 | DOI:10.1002/ajmg.b.30287
  • Parr, J.R., Lamb, J.A., Bailey, A.J., Monaco, A.P. and The International Molecular Genetic Study of Autism Consortium (IMGSAC). (2006). Response to paper by Molloy et al: Linkage on 21q and 7q in autism subset with regression. Molecular Psychiatry, 11(7), 617-619. eScholarID:85075 | DOI:10.1038/sj.mp.4001833

2005

  • BarnbyG, AbbottA, SykesN, MorrisA, WeeksD.E, MottR, Lamb J, BaileyA.J, MonacoA.P. (2005). Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of association at GRIN2A and ABAT. Am. J. Hum. Genet, 76(6), 950-966. eScholarID:1d17681 | DOI:10.1086/430454
  • Bonora,E., Lamb, J, Barnby,G., Sykes,N., Moberly,T., Beyer,K.S., Klauck,S.M., Poustka,F., Bacchelli,E., Blasi,F., Maestrini,E., Battaglia,A., Haracopos,D., Pedersen,L., Isager,T., Eriksen,G., Viskum,B., Sorensen,E.U., Brondum-Nielsen,K., Cotterill,R., Engeland,H., Jonge,M., Kemner,C., Steggehuis,K., Scherpenisse,M., Rutter,M., Bolton,P.F., Parr,J.R., Poustka,A., Bailey,A.J., Monaco,A.P. (2005). Mutation screening and association analysis of six candidate genes for autism on chromosome 7q. Eur. J. Hum. Genet, 13, 2, 198-207. eScholarID:1d17682 | DOI:10.1038/sj.ejhg.5201315
  • Lamb, J, Barnby,G., Bonora,E., Sykes,N., Bacchelli,E., Blasi,F., Maestrini,E., Broxholme,J., Tzenova,J., Weeks,D., Bailey,A.J., Monaco,A.P. (2005). Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects. J. Med. Genet, 42(2), 132-137. eScholarID:1d17683 | DOI:10.1136/jmg.2004.025668

2004

  • D'Adamo P, Bacchelli E, Blasi F, Lipp H, Toniolo D, Maestrini E, International Molecular Genetic Study of Autism Consortium (IMGSAC), Lamb J. (2004). DNA variants in the human RAB3A gene are not associated with autism. Genes Brain Behav, 3(2), 123-124. eScholarID:1d20702 | DOI:10.1111/j.1601-183X.2003.00058.x

2003

  • Bacchelli,E., Blasi,F., Biondolillo,M., Lamb, J, Bonora,E., Barnby,G., Parr,J., Beyer,K.S., Klauck,S.M., Poustka,A., Bailey,A.J., Monaco,A.P., Maestrini,E. (2003). Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Mol. Psychiatry, 8(11), 916-924. eScholarID:1d17679 | DOI:10.1038/sj.mp.4001340
  • Bonora,E., Beyer,K.S., Lamb, J, Parr,J.R., Klauck,S.M., Benner,A., Paolucci,M., Abbott,A., Ragoussis,I., Poustka,A., Bailey,A.J., Monaco,A.P. (2003). Analysis of reelin as a candidate gene for autism. Mol. Psychiatry, 8(10), 885-892. eScholarID:1d17680 | DOI:10.1038/sj.mp.4001310

2002

  • Beyer, K., Blasi, F., Bacchelli, E., Klauck, S., Maestrini, E., Poustka, A. & IMGSAC, I (2002). Mutation analysis of the coding sequence of the MECP2 gene in infantile autism. Hum Genet, 111(4-5), 305-309. eScholarID:54341 | PMID:12384770 | DOI:10.1007/s00439-002-0786-3
  • Bonora, E., Bacchelli, E., Levy, E., Blasi, F., Marlow, A., Monaco, A., Maestrini, E. & IMGSAC, I (2002). Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region. Mol Psychiatry, 7(3), 289-301. eScholarID:54343 | PMID:11920156 | DOI:10.1038/sj.mp.4001004
  • Lamb, J., Parr, J., Bailey, A. & Monaco, A (2002). Autism: in search of susceptibility genes. Neuromolecular Med, 2(1), 11-28. eScholarID:54367 | PMID:12230302 | DOI:10.1385/NMM:2:1:11
  • Newbury,D.F., Bonora,E., Lamb, J, Fisher,S.E., Lai,C.S., Baird,G., Jannoun,L., Slonims,V., Stott,C.M., Merricks,M.J., Bolton,P.F., Bailey,A.J., Monaco,A.P. (2002). FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am. J. Hum. Genet, 70(5), 1318-1327. eScholarID:1d17678 | DOI:10.1086/339931

2001

  • International Molecular Genetic Study of Autism Consortium. (2001). A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet, 69(3), 570-581. eScholarID:56481 | PMID:11481586 | DOI:10.1086/323264
  • International Molecular Genetic Study of Autism Consortium. (2001). Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet, 10(9), 973-982. eScholarID:56482 | PMID:11392322 | DOI:10.1093/hmg/10.9.973

2000

  • Lamb J, MooreJ, BaileyA, MonacoA.P. (2000). Autism: recent molecular genetic advances. Hum. Mol. Genet, 9(6), 861-868. eScholarID:1d17677
  • Ogilvie, C., Moore, J., Daker, M., Palferman, S., Docherty, Z. and IMGSAC. (2000). Chromosome 22q11 deletions are not found in autistic patients identified using strict diagnostic criteria. American Journal of Medical Genetics. Part a, 96, 15-17. eScholarID:56544 | DOI:10.1002/(SICI)1096-8628(20000207)96:1<15::AID-AJMG5>3.0.CO;2-M

1999

  • FisherS.E, MarlowA.J, Lamb J, MaestriniE, WilliamsD.F, RichardsonA.J, WeeksD.E, SteinJ.F, MonacoA.P. (1999). A quantitative-trait locus on chromosome 6p influences different aspects of developmental dyslexia. Am. J. Hum. Genet, 64(1), 146-156. eScholarID:1d17676
  • Maestrini, E., Lai, C., Marlow, A., Matthews, N., Wallace, S., Bailey, A., Cook, E. H., Weeks, D. E., Monaco, A. P. and IMGSAC. (1999). Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. American Journal of Medical Genetics, 88, 492-496. eScholarID:53935

1998

  • International Molecular Genetic Study of Autism Consortium. (1998). A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Human Molecular Genetics, 7, 571-578. eScholarID:53872

1994

  • Turner, N., Dolan, J., Grimsditch, D., Lamb, J., Worby, A., Murray, K., Coates, W. & Warrington, B (1994). Pulmonary effects of type V cyclic GMP specific phosphodiesterase inhibition in the anaesthetized guinea-pig. Br J Pharmacol, 111(4), 1047-1052. eScholarID:54304 | PMID:8032606
  • Turner, N., Lamb, J., Worby, A. & Murray, K (1994). Relaxation of guinea-pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside. Br J Pharmacol, 111(4), 1198-1204. eScholarID:54306 | PMID:8032589

Funding Bodies

Current research is supported by a grant from Autistica and a Medical Research Council PhD Studentship and President's Doctoral Scholar Award to Thomas Bleazard (start Sept 2013).

Contact details

Dr Janine Lamb

Senior Lecturer in Complex Human Genetics/Genomics
Director, Masters of Research in Translational Medicine

Janine.Lamb@manchester.ac.uk