Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations

Falk, Catherine T.; Rubinstein, Pablo

doi:10.1111/j.1469-1809.1987.tb00875.x

Cited by 579 publications

(380 citation statements)

References 9 publications

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“…Statistical tests involved calculation of Hardy-Weinberg equilibrium and the haplotype-based haplotype relative risk calculation 17 (HHRR) to allow a combined analysis 18 which may detect heterogeneity between samples, and the transmission disequilibrium test (TDT). The TDT was performed to look for association and linkage between the −1438A putative vulnerability Molecular Psychiatry allele and anorexia nervosa 19 and the related quantitative traits of minimum adult BMI, subtype of diagnosis, and age at onset, using the Q-TDT program.…”

Section: Discussionmentioning

confidence: 99%

The 5-HT2A −1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres

et al. 2002

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Keywords: eating disorder; serotonin; TDT (transmission disequilibrium test); QTL (quantitative trait loci)Several case-control association studies have raised the possibility that the A allele of a −1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar 2 = 0.29, df = 1, P = 0.59). Also, the haplotypebased haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre ( 2 Ͻ 2.15, df = 1, P Ͼ 0.14) and in the total sample ( 2 = 0.55, df = 1; P = 0.46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples ( 2 = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT 2A gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size). Molecular Psychiatry (2002) 7, 90-94.

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Section: Discussionmentioning

confidence: 99%

The 5-HT2A −1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres

et al. 2002

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“…For both single-marker and haplotype analysis, we calculated relative risk (RR) and PAR assuming a multiplicative model 43,44 in which the risk of the two alleles of haplotypes a person carries multiply. We calculated LD between pairs of SNPs using the standard definition of D′ (ref.…”

Section: Study Populationmentioning

confidence: 99%

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

et al. 2004

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NATURE GENETICS VOLUME 36 | NUMBER 3 | MARCH 2004 233Cardiovascular diseases (CVD) are the leading causes of death and disability in the developed world 1 , with an increasing prevalence due to the aging of the population and the obesity epidemic. More than 1 million deaths in the US alone were caused by myocardial infarction and stroke in 2003 (ref. 2). Some of the processes underlying myocardial infarction are now understood: it is generally attributed to atherosclerosis with arterial wall inflammation that ultimately leads to plaque rupture, fissure or erosion 3,4 . This process is known to involve diapedesis of monocytes across the endothelial barrier; activation of neutrophils, macrophage cells and platelets; and release of a variety of cytokines and chemokines 5,6 , but the genetic basis of the process has not yet been deciphered. Two different approaches have been used to search for genes associated with myocardial infarction. SNPs in candidate genes have been tested for association and have, in general, not been replicated or confer only a modest risk of myocardial infarction. Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect 7-9 . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.Here we report a genome-wide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction. Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. We confirmed the association of ALOX5AP with myocardial infarction in an independent cohort of British individuals with another haplotype. These results indicate that ALOX5AP is the first specific gene isolated that confers substantial population-attributable risk (PAR) of the complex traits of both myocardial infarction and stroke. We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13....

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“…Another advantage of a family analysis is parallel evaluation of the inheritance and allows indirect proof of the accuracy of the genotype methods (Falk et al 1987). For these reasons, ours was a family-based analysis.…”

Section: Methodsmentioning

confidence: 99%

TIM-3 polymorphisms in type 1 diabetes families

et al. 2008

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Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations

Cited by 579 publications

References 9 publications

The 5-HT2A −1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres

The 5-HT2A −1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

TIM-3 polymorphisms in type 1 diabetes families

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