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

Oexle, Konrad; Schormair, Barbara; Ried, Janina S.; Czamara, Darina; Heim, Katharina; Frauscher, Birgit; Högl, Birgit; Trenkwalder, Claudia; Fiedler, G. Martin; Thiery, Joachim; Lichtner, Peter; Prokisch, Holger; Specht, Michael; Müller-Myhsok, Bertram; Döring, Angela; Gieger, Christian; Peters, Annette; Wichmann, H.-Erich; Meitinger, Thomas and Winkelmann, Juliane (2013). Dilution of candidates: the case of iron-related genes in restless legs syndrome. European journal of human genetics, 21(4), pp. 410-414. Nature Publishing Group 10.1038/ejhg.2012.193

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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 = 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 = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 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 = 0.00085) but not in the second replication step (joint nominal P-value = 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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
UniBE Contributor:	Fiedler, Georg Martin
Subjects:	600 Technology > 610 Medicine & health
ISSN:	1018-4813
Publisher:	Nature Publishing Group
Language:	English
Submitter:	Barbara Keller
Date Deposited:	02 May 2014 09:21
Last Modified:	02 Mar 2023 23:24
Publisher DOI:	10.1038/ejhg.2012.193
PubMed ID:	22929029
URI:	https://boris.unibe.ch/id/eprint/48970