Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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23750121
TITLE
Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta-analyzed to date.
METHODS AND FINDINGS NlmCategory: RESULTS
We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 µg/dl increase in serum iron.
CONCLUSIONS NlmCategory: CONCLUSIONS
Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made.
DATE PUBLISHED
2013
HISTORY
PUBSTATUS PUBSTATUSDATE
ppublish 2013/06
received 2012/11/03
accepted 2013/04/24
epublish 2013/06/04
entrez 2013/06/11 06:00
pubmed 2013/06/12 06:00
medline 2014/03/22 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Pichler I Pichler Irene I Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. irene.pichler@eurac.edu
Del Greco M F Del Greco M Fabiola F
Gögele M Gögele Martin M
Lill CM Lill Christina M CM
Bertram L Bertram Lars L
Do CB Do Chuong B CB
Eriksson N Eriksson Nicholas N
Foroud T Foroud Tatiana T
Myers RH Myers Richard H RH
PD GWAS Consortium
Nalls M Nalls Michael M
Keller MF Keller Margaux F MF
International Parkinson's Disease Genomics Consortium
Wellcome Trust Case Control Consortium 2
Benyamin B Benyamin Beben B
Whitfield JB Whitfield John B JB
Genetics of Iron Status Consortium
Pramstaller PP Pramstaller Peter P PP
Hicks AA Hicks Andrew A AA
Thompson JR Thompson John R JR
Minelli C Minelli Cosetta C
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Plagnol Vincent V
Hernandez Dena G DG
Sharma Manu M
Sheerin Una-Marie UM
Saad Mohamad M
Simón-Sánchez Javier J
Schulte Claudia C
Lesage Suzanne S
Arepalli Sampath S
Barker Roger R
Ben-Shlomo Yoav Y
Berendse Henk W HW
Berg Daniela D
Bhatia Kailash K
de Bie Rob M A RM
Biffi Alessandro A
Bloem Bas B
Bochdanovits Zoltan Z
Bonin Michael M
Bras Jose M JM
Brockmann Kathrin K
Brooks Janet J
Burn David J DJ
Charlesworth Gavin G
Chen Honglei H
Chinnery Patrick F PF
Chong Sean S
Clarke Carl E CE
Cookson Mark R MR
Cooper J Mark JM
Corvol Jean Christophe JC
Counsell Carl C
Damier Philippe P
Dartigues Jean-François JF
Deloukas Panos P
Deuschl Günther G
Dexter David T DT
van Dijk Karin D KD
Dillman Allissa A
Durif Frank F
Dürr Alexandra A
Edkins Sarah S
Evans Jonathan R JR
Foltynie Thomas T
Gao Jianjun J
Gardner Michelle M
Gibbs J Raphael JR
Goate Alison A
Gray Emma E
Guerreiro Rita R
Harris Clare C
van Hilten Jacobus J JJ
Hofman Albert A
Hollenbeck Albert A
Holton Janice J
Hu Michele M
Huang Xuemei X
Huber Heiko H
Hudson Gavin G
Hunt Sarah E SE
Illig Thomas T
Lambert Jean-Charles JC
Langford Cordelia C
Lees Andrew A
Lichtner Peter P
Limousin Patricia P
Lopez Grisel G
Lorenz Delia D
McNeill Alisdair A
Moorby Catriona C
Moore Matthew M
Morris Huw R HR
Morrison Karen E KE
Mudanohwo Ese E
O'Sullivan Sean S SS
Pearson Justin J
Perlmutter Joel S JS
Pollak Pierre P
Post Bart B
Potter Simon S
Ravina Bernard B
Revesz Tamas T
Riess Olaf O
Rivadeneira Fernando F
Rizzu Patrizia P
Ryten Mina M
Sawcer Stephen S
Schapira Anthony A
Scheffer Hans H
Shaw Karen K
Shoulson Ira I
Sidransky Ellen E
Smith Colin C
Spencer Chris C A CC
Stockton Joanna D JD
Strange Amy A
Talbot Kevin K
Tanner Carlie M CM
Tashakkori-Ghanbaria Avazeh A
Trabzuni Daniah D
Traynor Bryan J BJ
Uitterlinden André G AG
Velseboer Daan D
Vidailhet Marie M
Walker Robert R
van de Warrenburg Bart B
Wickremaratchi Mirdhu M
Williams Nigel N
Williams-Gray Caroline H CH
Winder-Rhodes Sophie S
Martinez Maria M
Hardy John J
Heutink Peter P
Brice Alexis A
Gasser Thomas T
Singleton Andrew B AB
Wood Nicholas W NW
Donnelly Peter P
Barroso Ines I
Blackwell Jenefer M JM
Bramon Elvira E
Brown Matthew A MA
Casas Juan P JP
Corvin Aiden A
Deloukas Panos P
Duncanson Audrey A
Jankowski Janusz J
Markus Hugh S HS
Mathew Christopher G CG
Palmer Colin N A CN
Plomin Robert R
Rautanen Anna A
Sawcer Stephen J SJ
Trembath Richard C RC
Viswanathan Ananth C AC
Wood Nicholas W NW
Spencer Chris C A CC
Band Gavin G
Bellenguez Céline C
Freeman Colin C
Hellenthal Garrett G
Giannoulatou Eleni E
Pirinen Matti M
Pearson Richard R
Strange Amy A
Su Zhan Z
Vukcevic Damjan D
Donnelly Peter P
Langford Cordelia C
Hunt Sarah E SE
Edkins Sarah S
Gwilliam Rhian R
Blackburn Hannah H
Bumpstead Suzannah J SJ
Dronov Serge S
Gillman Matthew M
Gray Emma E
Hammond Naomi N
Jayakumar Alagurevathi A
McCann Owen T OT
Liddle Jennifer J
Potter Simon C SC
Ravindrarajah Radhi R
Ricketts Michelle M
Waller Matthew M
Weston Paul P
Widaa Sara S
Whittaker Pamela P
Barroso Ines I
Deloukas Panos P
McCarthy Mark I MI
Ouwehand Willem H WH
Radhakrishnan Aparna A
Sambrook Jennifer J
Toniolo Daniela D
Traglia Michela M
Camaschella Clara C
Metspalu Andres A
Esko Tonu T
Gieger Christian C
Ried Janina J
Meitinger Thomas T
Oexle Konrad K
Winkelmann Juliane J
Swinkels Dorine D
Vermeulen Sita S
van Duijn Cornelia C
Broer Linda L
Beilby John J
Hui Jennie J
Anderson Denise D
Visscher Peter P
Martin Nick N
JOURNAL
VOLUME: 10
ISSUE: 6
TITLE: PLoS medicine
ISOABBREVIATION: PLoS Med.
YEAR: 2013
MONTH:
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1549-1676
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: PLoS Med
COUNTRY: United States
ISSNLINKING: 1549-1277
NLMUNIQUEID: 101231360
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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ErratumIn PLoS Med. 2013 Jun;10(6). doi:10.1371/annotation/c4d81646-0c0e-4a3e-9425-b220bae2d8b6 19820699
GRANTS
GRANTID AGENCY COUNTRY
083948/Z/07/Z Wellcome Trust United Kingdom
090532 Wellcome Trust United Kingdom
F-1202 Parkinson's UK United Kingdom
G-0909 Parkinson's UK United Kingdom
G0700943 Medical Research Council United Kingdom
G0802462 Medical Research Council United Kingdom
G1100479 Medical Research Council United Kingdom
J-0901 Parkinson's UK United Kingdom
NS057105 NINDS NIH HHS United States
R01 NS076843 NINDS NIH HHS United States
R01-NS076843 NINDS NIH HHS United States
R44 HG006981 NHGRI NIH HHS United States
RR024992 NCRR NIH HHS United States
UL1 RR024992 NCRR NIH HHS United States
UL1 TR000448 NCATS NIH HHS United States
WT089698 Wellcome Trust United Kingdom
WT089698/Z/09/Z Wellcome Trust United Kingdom
Z01-AG000949-02 NIA NIH HHS United States
Z01-ES101986 NIEHS NIH HHS United States
Department of Health United Kingdom
Intramural NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Iron blood
Mendelian Randomization Analysis blood
Parkinson Disease genetics
Risk Factors genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
E1UOL152H7 Iron
OTHER ID's
OTHERID SOURCE
PMC3672214 NLM