A remark on rare variants

Oexle, Konrad

doi:10.1038/jhg.2010.9

Cited by 8 publications

(6 citation statements)

References 29 publications

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“…Detection of such variants will be difficult and, besides next-generation sequencing, necessitate specific study design. 28 A further possible bias of our study resides in the fact that our sampling scheme for the RLS GWAS (on which we based the discovery step of this study) excluded cases that had anemia because of iron deficiency. Although this exclusion criterion only affected cases with severe iron deficiency (which already caused anemia), our study would possibly have been more powerful without this criterion.…”

Section: Discussionmentioning

confidence: 99%

Dilution of candidates: the case of iron-related genes in restless legs syndrome

et al. 2012

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Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n ¼ 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P ¼ 5 Â 10 À4 . Two population cohorts (KORA F3 and F4 with together n ¼ 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P ¼ 0.00085) but not in the second replication step (joint nominal P-value ¼ 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes. Keywords: restless legs syndrome; iron parameters; MEIS1 haplotype; power calculation; linear regression; logistic regression INTRODUCTIONRestless legs syndrome (RLS) 1 is a sensory-motor disorder characterized by an urge to move and unpleasant sensations in the lower limbs at rest. In Caucasians, RLS is present in up to 10% of the population. 2,3 Pregnancy, uremia, celiac disease, and iron deficiency are considered to be risk factors. 4 RLS also has a considerable heritability and is associated with multiple genetic risk factors. Genome-wide association studies 5-10 identified variants in six loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, PTPRD, and TOX3/non-coding RNA.Aiming for the identification of further genetic risk factors of RLS, we addressed the apparent relation of RLS susceptibility to iron metabolism and iron availability 11 that has been explained by cerebral iron being crucial in the etiology of RLS. 12 We therefore tested the SNPs at the loci of a candidate set of genes known to be involved in iron metabolism for association with RLS. Vice versa, we asked whether RLS genes are involved in iron metabolism because the RLSassociated SNP rs3923809 at the BTBD9 locus has previously been reported to be associated with the serum level of ferritin in a study on RLS subjects and their relatives. 6

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Section: Discussionmentioning

confidence: 99%

Dilution of candidates: the case of iron-related genes in restless legs syndrome

et al. 2012

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“…68 However, not all approaches to linkage analysis are very powerful, and this is especially true for non-parametric approaches involving small families 69, 70 , although transmission/disequilibrium tests may have merit in the analysis of rare variants. 71 In addition, linkage analysis approaches not only come with the often difficult and expensive need to sample family members, but many phenotypes may not exhibit familial aggregation, undermining the motivation to consider family-based studies 10 .…”

Section: Specific Analysis Modelsmentioning

confidence: 99%

Statistical analysis strategies for association studies involving rare variants

et al. 2010

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The limitations of genome-wide association (GWA) studies that focus on the phenotypic influence of common genetic variants have motivated human geneticists to consider the contribution of rare variants to phenotypic expression. The increasing availability of high-throughput sequencing technology has enabled studies of rare variants, but will not be sufficient for their success since appropriate analytical methods are also needed. We consider data analysis approaches to testing associations between a phenotype and collections of rare variants in a defined genomic region or set of regions. Ultimately, although a wide variety of analytical approaches exist, more work is needed to refine them and determine their properties and power in different contexts.

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“…The most parsimonious approach is to test individual variants for trait effects. However, this would certainly require populations much larger than the Framingham cohort because these variants will be sufficiently rare that detection of their effects will require the power afforded by a sufficient number of carriers [49]. If allelic heterogeneity is a feature of most genes contributing to rare variation, as Pritchard's modeling and the Framingham investigation suggest, then more often than not many variants in each gene will need to be tested individually.…”

Section: Rare Variants Step Forwardmentioning

confidence: 99%

The Genetics of Blood Pressure and Hypertension: The Role of Rare Variation

Doris

2010

Cardiovascular Therapeutics

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Summary The role of heredity in influencing blood pressure and risk of hypertension is well recognized. However, progress in identifying specific genetic variation that contributes to heritability is very limited. This is in spite of completion of the human genome sequence, the development of extraordinary amounts of information about genome sequence variation and the investigation of blood pressure inheritance in linkage analysis, candidate gene studies and, most recently genome-wide association studies. This paper considers the progress of this research and the obstacles that have been encountered. This work has made clear that the genetic architecture of blood pressure regulation in the population is not likely to be shaped by commonly occurring genetic variation in a discrete set of blood pressure-influencing genes. Rather heritability may be accounted for by rare variation that has its biggest impact within pedigrees rather than on the population at large. Rare variants in a wide range of genes are likely to be the focus of high blood pressure genetics for the next several years and the emerging strategies that can be applied to uncover this genetic variation and the problems that must confronted are considered.

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A remark on rare variants

Cited by 8 publications

References 29 publications

Dilution of candidates: the case of iron-related genes in restless legs syndrome

Dilution of candidates: the case of iron-related genes in restless legs syndrome

Statistical analysis strategies for association studies involving rare variants

The Genetics of Blood Pressure and Hypertension: The Role of Rare Variation

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