Abstract
The involvement of genetic factors in the etiology of autism has been clearly established. We undertook a genome-wide search for regions containing susceptibility genes for autism in 12 subjects with childhood autism and related pervasive developmental disorders (PDDs) and 44 controls from the relatively isolated population of the Faroe Islands. In total, 601 microsatellite markers distributed throughout the human genome with an average distance of 5.80 cM were genotyped, including 502 markers in the initial scan. The Faroese population structure and genetic relatedness of cases and controls were also evaluated. Based on a combined approach, including an assumption-free test as implemented in CLUMP, Fisher's exact test for specific alleles and haplotypes, and IBD0 probability calculations, we found association between autism and microsatellite markers in regions on 2q, 3p, 6q, 15q, 16p, and 18q. The most significant finding was on 3p25.3 (PT1=0.00003 and PT4=0.00007), which was also supported by other genetic studies. Furthermore, no evidence of population substructure was found, and a higher degree of relatedness among cases could not be detected, decreasing the risk of inflated P-values. Our data suggest that markers in these regions are in linkage disequilibrium with genes involved in the etiology of autism, and we hypothesize susceptibility genes for autism and related PDDs to be localized within these regions.
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References
World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic criteria for research. World Health Organization: Geneva, 1993.
Bolton P, Macdonald H, Pickles A, Rios P, Goode S, Crowson M et al. A case–control family history study of autism. J Child Psychol Psychiatry 1994; 35: 877–900.
Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med 1995; 25: 63–77.
Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim C-H et al. Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. Am J Hum Genet 1995; 57: 717–726.
Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J et al. A genomic screen of autism: evidence for a multilocus etiology. Am J Hum Genet 1999; 65: 493–507.
IMGSAC. A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 2001; 69: 570–581.
Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E et al. Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 2001; 68: 1514–1520.
Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL et al. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 2004; 161: 662–669.
Badner JA, Gershon ES . Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7. Mol Psychiatry 2002; 7: 56–66.
Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 2005; 10: 563–571.
Bolton PF, Dennis NR, Browne CE, Thomas NS, Veltman MW, Thompson RJ et al. The phenotypic manifestations of interstitial duplications of proximal 15q with special reference to the autistic spectrum disorders. Am J Med Genet 2001; 105: 675–685.
Simic M, Turk J . Autistic spectrum disorder associated with partial duplication of chromosome 15; three case reports. Eur Child Adolesc Psychiatry 2004; 13: 389–393.
Muhle R, Trentacoste SV, Rapin I . The genetics of autism. Pediatrics 2004; 113: e472–e486.
Peltonen L, Jalanko A, Varilo T . Molecular genetics of the Finnish disease heritage. Hum Mol Genet 1999; 8: 1913–1923.
Gianfrancesco F, Esposito T, Ombra MN, Forabosco P, Maninchedda G, Fattorini M et al. Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. Am J Hum Genet 2003; 72: 1479–1491.
Auranen M, Varilo T, Alen R, Vanhala R, Ayers K, Kempas E et al. Evidence for allelic association on chromosome 3q25–27 in families with autism spectrum disorders originating from a subisolate of Finland. Mol Psychiatry 2003; 8: 879–884.
Ylisaukko-Oja T, Nieminen-Von Wendt T, Kempas E, Sarenius S, Varilo T, Wendt LL et al. Genome-wide scan for loci of Asperger syndrome. Mol Psychiatry 2004; 9: 161–168.
Jorgensen TH, Buttenschon HN, Wang AG, Als TD, Borglum AD, Ewald H . The origin of the isolated population of the Faroe Islands investigated using Y chromosomal markers. Hum Genet 2004; 115: 19–28.
West JF . Faroe: The Emergence of a Nation. Hurst: London, 1972.
Schwartz M, Sorensen N, Brandt NJ, Hogdall E, Holm T . High incidence of cystic fibrosis on the Faroe Islands: a molecular and genealogical study. Hum Genet 1995; 95: 703–706.
Santer R, Kinner M, Steuerwald U, Kjaergaard S, Skovby F, Simonsen H et al. Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands. Eur J Hum Genet 2001; 9: 388–391.
Jeganathan D, Chodhari R, Meeks M, Faeroe O, Smyth D, Nielsen K et al. Loci for primary ciliary dyskinesia map to chromosome 16p12.1–12.2 and 15q13.1–15.1 in Faroe Islands and Israeli Druze genetic isolates. J Med Genet 2004; 41: 233–240.
Degn B, Lundorf MD, Wang A, Vang M, Mors O, Kruse TA et al. Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands. Mol Psychiatry 2001; 6: 450–455.
Als TD, Dahl HA, Flint TJ, Wang AG, Vang M, Mors O et al. Possible evidence for a common risk locus for bipolar affective disorder and schizophrenia on chromosome 4p16 in patients from the Faroe Islands. Mol Psychiatry 2004; 9: 93–98.
Jorgensen TH, Degn B, Wang AG, Vang M, Gurling H, Kalsi G et al. Linkage disequilibrium and demographic history of the isolated population of the Faroe Islands. Eur J Hum Genet 2002; 10: 381–387.
Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 2000; 30: 205–223.
Lord C, Rutter M, Le Couteur A . Autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994; 24: 659–685.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. DSM-IV. 4th edn. American Psychiatric Association: Washington, DC, 1994.
Escamilla MA, McInnes LA, Service SK, Spesny M, Reus VI, Molina J et al. Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18. Am J Med Genet 2001; 105: 207–213.
Bourgain C, Hoffjan S, Nicolae R, Newman D, Steiner L, Walker K et al. Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus. Am J Hum. Genet 2003; 73: 612–626.
Bourgain C, Genin E . Complex trait mapping in isolated populations: Are specific statistical methods required? Eur J Hum Genet 2005; 13: 698–706.
Queller DC, Goodnight KF . Estimating relatedness using genetic markers. Evolution 1989; 43: 258–275.
Hardy OJ, Vekemans X . SPAGEDi: a versatile computer program to analyse spatial genetic structure at the individual or population levels. Mol Ecol Notes 2002; 2: 618–620.
Rousset F . Genetic differentiation between individuals. J Evol Biology 2000; 13: 58–62.
Weir B . Genetic Data Analysis II. Sinauer Associates: Massachusetts, Sunderland, Date: 1996.
Pritchard JK, Stephens M, Donnelly P . Inference of population structure using multilocus genotype data. Genetics 2000; 155: 945–959.
Falush D, Stephens M, Pritchard JK . Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 2003; 164: 1567–1587.
Sham PC, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.
Houwen RH, Baharloo S, Blankenship K, Raeymaekers P, Juyn J, Sandkuijl LA et al. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet 1994; 8: 380–386.
Durham LK, Feingold E . Genome scanning for segments shared identical by descent among distant relatives in isolated populations. Am J Hum Genet 1997; 61: 830–842.
Shao Y, Wolpert CM, Raiford KL, Menold MM, Donnelly SL, Ravan SA et al. Genomic screen and follow-up analysis for autistic disorder. Am J Med Genet 2002; 114: 99–105.
McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K et al. Genome-wide and ordered-subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet 2005; 6: 1.
Hauser ER, Boehnke M, Guo SW, Risch N . Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genet Epidemiol 1996; 13: 117–137.
Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N et al. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry 2004; 9: 144–150.
Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair study. Hum Mol Genet 1999; 8: 805–812.
International Molecular Genetic Study of Autism Consortium. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. Hum Mol Genet 1998; 7: 571–578.
Barnby G, Abbott A, Sykes N, Morris A, Weeks DE, Mott R et al. 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 2005; 76: 950–966.
Hebebrand J, Martin M, Korner J, Roitzheim B, de Braganca K, Werner W et al. Partial trisomy 16p in an adolescent with autistic disorder and Tourette's syndrome. Am J Med Genet 1994; 54: 268–270.
Carrasco Juan JL, Cigudosa JC, Otero GA, Acosta Almeida MT, Garcia Miranda JL . De novo trisomy 16p. Am J Med Genet 1997; 68: 219–221.
Hellings JA, Hossain S, Martin JK, Baratang RR . Psychopathology, GABA, and the Rubinstein-Taybi syndrome: a review and case study. Am J Med Genet 2002; 114: 190–195.
Finelli P, Natacci F, Bonati MT, Gottardi G, Engelen JJ, Die-Smulders CE et al. FISH characterisation of an identical (16)(p11.2p12.2) tandem duplication in two unrelated patients with autistic behaviour. J Med Genet 2004; 41: e90.
Lauritsen MB, Ewald H . The genetics of autism. Acta Psychiatr Scand 2001; 103: 411–427.
The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–1315.
Serajee FJ, Nabi R, Zhong H, Mahbubul Huq AH . Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. J Med Genet 2003; 40: e119.
Barrett S, Beck JC, Bernier R, Bisson E, Braun TA, Casavant TL et al. An autosomal genomic screen for autism. Am J Med Genet 1999; 88: 609–615.
Shastry BS . Molecular genetics of autism spectrum disorders. J Hum Genet 2003; 48: 495–501.
Constantino JN, Todd RD . Autistic traits in the general population: a twin study. Arch Gen Psychiatry 2003; 60: 524–530.
Lord C, Pickles A, McLennan J, Rutter M, Bregman J, Folstein S et al. Diagnosing autism: analyses of data from the autism diagnostic interview. J Autism Dev Disord 1997; 27: 501–517.
de Bildt A, Sytema S, Ketelaars C, Kraijer D, Mulder E, Volkmar F et al. Interrelationship between autism diagnostic observation schedule-generic (ADOS-G), autism diagnostic interview-revised (ADI-R), and the diagnostic and statistical manual of mental disorders (DSM-IV-TR) classification in children and adolescents with mental retardation. J Autism Dev Disord 2004; 34: 129–137.
Newman DL, Hoffjan S, Bourgain C, Abney M, Nicolae RI, Profits ET et al. Are common disease susceptibility alleles the same in outbred and founder populations? Eur J Hum Genet 2004; 12: 584–590.
Taillon-Miller P, Bauer-Sardina I, Saccone NL, Putzel J, Laitinen T, Cao A et al. Juxtaposed regions of extensive and minimal linkage disequilibrium in human Xq25 and Xq28. Nat Genet 2000; 25: 324–328.
Eaves IA, Merriman TR, Barber RA, Nutland S, Tuomilehto-Wolf E, Tuomilehto J et al. The genetically isolated populations of Finland and Sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes. Nat Genet 2000; 25: 320–323.
Shifman S, Darvasi A . The value of isolated populations. Nat Genet 2001; 28: 309–310.
Lonjou C, Zhang W, Collins A, Tapper WJ, Elahi E, Maniatis N et al. Linkage disequilibrium in human populations. Proc Natl Acad Sci USA 2003; 100: 6069–6074.
Peltonen L, Palotie A, Lange K . Use of population isolates for mapping complex traits. Nat Rev Genet 2000; 1: 182–190.
Pericak-Vance MA . Linkage disequilibrium and allelic association. In: Haines JL, Pericak-Vance MA (eds). Approaches to Gene Mapping in Complex Human Diseases. John Wiley & Sons: New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1998; 323–334.
Wright AF, Teague PW, Bruford E, Carothers A . Problems in dealing with linkage heterogeneity in autosomal recessive forms of retinitis pigmentosa. In: Pawlowitzki I-H, Edwards JH, Thompson EA (eds). Genetic Mapping of Disease Genes. Academic Press Inc.: San Diego, London, NY, 1997; 255–272.
Ober C, Cox NJ . The genetics of asthma. Mapping genes for complex traits in founder populations. Clin Exp Allergy 1998; 28 (Suppl 1): 101–105.
Speer MC . Basic concepts in genetics. In: Haines JL, Pericak-Vance MA (eds). Approaches to Gene Mapping in Complex Human Diseases. John Wiley & Sons: New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1998; 17–52.
Acknowledgements
We thank The Faroese association for autism, and the late chairman Mrs ‘Margrethe Joensen-Næs for their participation in this study. We also thank psychologist Lennart Pedersen, National Centre for Autism, Copenhagen, for diagnostic assessments, statistician Leslie Foldager, Centre for Basic Psychiatric Research, Aarhus University Hospital, Aarhus, for statistical advice, and research assistant Agata El Daoud for help with the genotyping. In addition, we thank assistant professors Thomas Bataillon and Roald Forsberg, The Bioinformatics Research Centre (BiRC), University of Aarhus and associate professor Jes Søe Petersen, Department of Population Biology, University of Copenhagen, for discussion of population genetics issues. This work was supported by The Danish Medical Research Council (Grant Number 9601887); The Lundbeck Foundation (Grants Numbers 39/98 and 59/99); Puljen til Styrkelse af Psykiatrisk Forskning i Aarhus Amt; Psykiatrisk forsknings fond; Ministry of Education, Culture and Research, The Faroese Government; Research Fund of the Faroese Savings Bank, Torshavn, Faroe Islands; Danish Hospital Foundation for Medical Research, Region of Copenhagen, the Faroe Islands and Greenland.
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Lauritsen, M., Als, T., Dahl, H. et al. A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands. Mol Psychiatry 11, 37–46 (2006). https://doi.org/10.1038/sj.mp.4001754
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