American Journal of Medical Genetics (Neuropsychiatric Genetics) 105:163±167 (2001) Rapid Publication Further Evidence for Linkage of Gilles de la Tourette Syndrome (GTS) Susceptibility Loci on Chromosomes 2p11, 8q22, and 11q23-24 in South African Afrikaners Ingrid Simonic, 1 Dale R. Nyholt, 2 George S. Gericke, 1 Derek Gordon, 2 Naomichi Matsumoto, 3 David H. Ledbetter, 3 Jurg Ott, 2 * and James L. Weber 4 1 MRC Neurogenetics Research Initiative, Pretoria, South Africa 2 Laboratory of Statistical Genetics, Rockefeller University, New York, New York 3 Department of Human Genetics, The University of Chicago, Chicago, Illinois 4 Center for Medical Genetics, Marsh®eld Medical Research Foundation, Marsh®eld, Wisconsin Utilizing DNA samples from 91 Afrikaner nuclear families with one or more affected children, ®ve genomic regions on chromo- somes 2p, 8q, 11q, 20q, and 21q that gave evidence for association with GTS in pre- vious case-control association studies were investigated for linkage and association with GTS. Highly polymorphic markers with mean heterozygosity of 0.77 were typed and resulting genotypes evaluated using single marker transmission disequilibrium (TDT), single marker haplotype relative risk (HRR), and multi-marker ``extended'' TDT and HRR methods. Single marker TDT analysis showed evidence for linkage or association, with p-values near 0.05, for markers D2S139, GATA28F12, and D11S1377 on chromosomes 2p11, 8q22 and 11q23-24, respectively. Extended, two-locus TDT and HRR analysis provided further evidence for linkage or association on chro- mosome 2 with p-values of 0.007 and 0.025, and chromosome 8 with p-values of 0.059 and 0.013, respectively. These results pro- vide important additional evidence for the location of GTS susceptibility loci. ß 2001 Wiley-Liss, Inc. INTRODUCTION While the etiology of Gilles de la Tourette syndrome (GTS) Ða childhood-onset neurologic disorder charac- terized by chronic involuntary movements (both motor and vocal tics at the time of diagnosis)Ðremains hidden, it has a strong genetic component [Price et al., 1985]. According to recent complex segregation analyses, the susceptibility for GTS is more complicated than previously suggested, conveyed by an additive major locus in combination with a multifactorial back- ground [Walkup et al., 1996]. A failure to identify GTS- linked genetic loci in large, multiple affected kindreds (no LOD > 2) [Barr et al., 1999] motivated the redirection of gene-mapping efforts toward allele-shar- ing methods and linkage disequilibrium (LD) studies in genetically isolated populations. Lander and Kruglyak [1995] proposed stringent guidelines for the assignment of genome-wide signi®- cance levels in linkage studies to diminish the rates of false positive results. However, in case-control LD studies, because of the danger of spurious associations due to mismatching of controls and population admix- ture, consistent replication may be the best evidence for a true association [Kidd, 1993]. Our previous whole-genome search for association with GTS among Afrikaners with 1,167 short tandem repeat polymorphisms, using a cross-sectional case- control strategy, DNA pooling, and follow-up individual typing of two independent samples, resulted in the identi®cation of 15 markers at 11 chromosomal regions showing signi®cant allele distribution differences between the two groups [Simonic et al., 1998]. For the reasons outlined above, our current study was designed as an attempt to replicate our previous results. Therefore, in this study, we collected additional independent affected individuals and their parents Grant sponsor: The Tourette Syndrome Association; National Institute of Mental Health; Grant number: MH44292. *Correspondence to: Jurg Ott, Laboratory of Statistical Genet- ics, Rockefeller University, New York, NY 10021. E-mail: ott@linkage.rockefeller.edu Received 20 December 1999; Accepted 27 November 2000 Published online 23 February 2001 ß 2001 Wiley-Liss, Inc.