Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies.

Single nucleotide polymorphisms (SNP) may be used in case-control designs to test for association between a SNP marker and a disease. Such designs may assume that the genotype data are reported without error. Our goal is quantifying the effects that errors have on sample size for case-control studies with haplotypes formed by a disease locus and a SNP marker locus in the presence of linkage disequilibrium (LD). We consider the effects of a recently published error model on 2x3 chi-square analysis. We study the joint relation of LD and errors with sample size for three specific genetic disease models and two settings each of marker allele frequencies (total of 6 studies). Minimal sample size necessary for fixed asymptotic power is estimated as a 4th degree polynomial in the variables S (error) and D' (LD measure) via a backward step-wise regression. We find that increased error rates lower power. In all studies, we observe that LD and errors interact in a non-linear fashion. In particular, regression analyses shows that several higher order interaction terms have coefficients significantly different from 0 in each study, with fraction of variance explained greater than 0.9999. Finally, the increase in sample size necessary to maintain constant asymptotic power and level of significance as a function of S is smallest when D' = 1 (perfect LD). The increase grows monotonically as D' decreases to 0.5 for all studies.

Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.

Two approaches for consolidating results from genome scans of complex traits: selection methods and scan statistics.

This work has two purposes: (i) empirically selecting levels of significance that maximize the fraction of markers close to a gene (hit rate) when performing linkage analyses of simulated data and (ii) evaluating the utility of a previously reported scan statistic on the same data. Genotype data were simulated from a trait model of seven susceptibility genes. For purpose (i), five statistics were evaluated on all marker loci in fifty replicates; two-point lod and heterogeneity lod scores maximized over dominance (mlod, mhlod), a multi-allelic TDT test, an affected sib-pair test (ASP), and a model-free test on all sib-pairs (ALL_SIBS). Within each replicate the fraction of markers (hit rate) significant at specified levels of significance and also (a) within fifty markers of, or (b) on the same chromosome as a major gene was calculated. For purpose (ii), scan statistics of length 15 were calculated for each chromosome and their empirical significance levels estimated on the basis of 500 replicates generated under no linkage. The scan statistic was applied to the mhlod scores from one replicate (Replicate 5). Empirical p-values for the scan statistic were determined by computing mhlod scores on 500 replicates of simulated null data. For purpose (i), significance levels between 0.001 and 0.01 had the greatest hit rate for all five methods and both criteria. For criterion (a) at the 0.001 level of significance, both mlod and mhlod displayed the highest hit rates, approximately 0.4 for each. For criterion (b), all methods but ALL_SIBS and ASP had hit rates ranging between 0.4 and 0.5. For purpose (ii), the scan statistic proved equally or more powerful than the single-locus statistic for two of the seven susceptibility genes while the remaining five genes were not detected.

Mapping of a gene for severe pediatric gastroesophageal reflux to chromosome 13q14.

CONTEXT: Gastroesophageal reflux (GER) has not previously been widely regarded as a hereditary disease. A few reports have suggested, however, that a genetic component may contribute to the incidence of GER, especially in its severe or chronic forms. OBJECTIVE: To identify a genetic locus that cosegregates with a severe pediatric GER phenotype in families with multiple affected members. DESIGN: A genome-wide scan of families affected by severe pediatric GER using polymorphic microsatellite markers spaced at an average of 8 centimorgans (cM), followed by haplotyping and by pairwise and multipoint linkage analyses. SETTING: General US community, with research performed in a university tertiary care hospital. SUBJECTS: Affected and unaffected family members from 5 families having multiple individuals affected by severe pediatric GER, identified through a patient support group. MAIN OUTCOME MEASURES: Determination of inheritance patterns and linkage of a genetic locus with the severe pediatric GER phenotype by logarithm-of-odds (lod) score analysis, considering a lod score of 3 or greater as evidence of linkage. RESULTS: In these families, severe pediatric GER followed an autosomal dominant hereditary pattern with high penetrance. A gene for severe pediatric GER was mapped to a 13-cM region on chromosome 13q between microsatellite markers D13S171 and D13S263. A maximum multifamily 2-point lod score of 5.58 and a maximum multifamily multipoint lod score of 7.15 were obtained for marker D13S1253 at map position 35 cM when presumptively affected persons were modeled as unknown (a maximum multipoint score of 4.88 was obtained when presumptively affected persons were modeled as unaffected). CONCLUSION: These data suggest that a gene for severe pediatric GER maps to chromosome 13q14. JAMA. 2000;284:325-334