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Progress of a full-genome scan for predisposition loci for affective disorder in the Old Order Amish is reported. LOD-score results have been previously published for 51 loci on chromosomes 1 and 11, collectively. The present report contains results for an additional 367 loci throughout the genome with extensive coverage on chromosomes 1, 2, 3, 4, 6, 7, 9, 10, 13, 14, 18, 19, and 21 (average marker density for these chromosomes = 10.7 cM). Analyses were conducted in a four-stage process: (1) two-point LOD scores were calculated for all loci under a dominant model with reduced penetrance, consistent with results of segregation analyses of these pedigrees; (2) a screen for the sharing of alleles in similarly affected individuals was used to highlight areas potentially important for further analysis; (3) the preceding areas and markers on densely covered chromosomes were analyzed using the affected-pedigree-member (APM) method; and (4) the sharing of extended haplotypes in affected individuals was examined in areas showing apparent clustering of significant allele sharing as assessed by the APM method. Of the 367 markers analyzed, no statistically significant LOD scores resulted. Some degree (P < .05) of allele sharing was found at 74 loci, and 3.8% of all markers analyzed (N = 14) passed more stringent significance criteria suggestive of linkage (P < or = .001 for at least one of the weighting functions). Multilocus APM and detailed exploration of extended haplotype sharing in areas highlighted by the APM analyses provided methods for more informative exploration of potentially suggestive results but did not identify areas clearly involved in the etiology of affective disorder in this population.

To investigate the transmission of Tourette syndrome (TS) and associated disorders within families, complex segregation analysis was performed on family study data obtained from 53 independently ascertained children and adolescents with TS and their 154 first-degree relatives. The results suggest that the susceptibility for TS is conveyed by a major locus in combination with a multifactorial background. Other models of inheritance were definitively rejected, including strictly polygenic models, all single major locus models, and mixed models with dominant and recessive major loci. The frequency of the TS susceptibility allele was estimated to be .01. The major locus accounts for over half of the phenotypic variance for TS, whereas the multifactorial background accounts for approximately 40% of phenotypic variance. Penetrance estimates suggest that all individuals homozygous for the susceptibility allele at the major locus are affected, whereas only 2.2% of males and 0.3% of females heterozygous at the major locus are affected. Of individuals affected with TS, approximately 62% are heterozygous and approximately 38% are homozygous at the major locus. While none of the families had two parents affected with TS, 19% of families had two parents affected with the broader, phenotype, which includes TS, chronic tic disorder, or obsessive-compulsive disorder.