ORIGINAL ARTICLE A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands MB Lauritsen 1 , TD Als 1 , HA Dahl 2 , TJ Flint 1 , AG Wang 3,4 , M Vang 4 , TA Kruse 2 , H Ewald 1,5 and O Mors 1 1 Centre for Basic Psychiatric Research, Psychiatric Hospital in Aarhus, Aarhus University Hospital, Risskov, Denmark; 2 Department of Clinical Biochemistry and Genetics, Odense University Hospital, Odense C, Denmark; 3 Department of Psychiatry, Amager Hospital, Copenhagen University Hospital, Copenhagen S, Denmark and 4 Department of Psychiatry, Landssju ` krahusid (National Hospital), Torshavn, Faroe Islands 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 IBD 0 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 (P T1 ¼ 0.00003 and P T4 ¼ 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. Molecular Psychiatry (2006) 11, 37–46. doi:10.1038/sj.mp.4001754; published online 4 October 2005 Keywords: genome-wide scan; association mapping; population isolate; haplotype sharing; susceptibility locus, autism Introduction Childhood autism is a pervasive neurodevelopmental disorder with onset of symptoms before the age of 3 years. The symptoms include severe impairments of communicative and social skills, together with stereo- typed and repetitive behavior. 1 Related disorders falling short of strict diagnostic criteria for childhood autism comprise Asperger’s syndrome, atypical aut- ism, and pervasive developmental disorder. Based on family and twin studies there is strong evidence of a genetic component. 2,3 The mode of inheritance is unknown, but a polygenic model has been suggested with estimates of the number of genes involved, ranging from three to more than 15 genes. 4,5 Based on genome-wide scans, screening of possible candidate genes, and studies of association between autism and chromosome abnormalities, candidate regions of autism have been suggested on chromosome 2q, 6–8 7q, 9,10 and 15q. 11,12 However, no susceptibility genes have yet been identified, and except for a few specific etiological factors like the fragile X syndrome, tuberous sclerosis, and maternally inherited duplica- tion of 15q11–13, the etiology of autism is largely unknown. 13 The use of isolated populations is a powerful approach in the search for disease genes and has facilitated the identification of candidate chromo- some regions involved in monogenic diseases 14 and in some complex diseases, for example, uric acid nephrolithiasis. 15 Isolated populations have also been used to study susceptibility genes for autism-spec- trum disorders in Finland, and evidence for a susceptibility locus was found on chromosome 3q25–27, 16 in addition to evidence for risk loci for Asperger’s syndrome on 1q21–22, 3p14–24, and 13q31–33. 17 We used the isolated population of the Faroe Islands to search for susceptibility genes of autism. The Faroe Islands are situated in the North Atlantic Received 9 November 2004; revised 22 August 2005; accepted 23 August 2005; published online 4 October 2005 Correspondence: Dr MB Lauritsen, Centre for Basic Psychiatric Research, Aarhus University Hospital, Skovagervej 2, DK-8240 Risskov, Denmark. E-mail: mbl@dadlnet.dk 5 In respectful memory of Professor Henrik Ewald 1958–2004. Molecular Psychiatry (2006) 11, 37–46 & 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00 www.nature.com/mp