title: Genome-wide association study of blood lead shows multiple associations near ALAD.
abstract: Exposure to high levels of environmental lead, or biomarker evidence of high body lead content, is associated with anaemia, developmental and neurological deficits in children, and increased mortality in adults. Adverse effects of lead still occur despite substantial reduction in environmental exposure. There is genetic variation between individuals in blood lead concentration but the polymorphisms contributing to this have not been defined. We measured blood or erythrocyte lead content, and carried out genome-wide association analysis, on population-based cohorts of adult volunteers from Australia and UK (N = 5433). Samples from Australia were collected in two studies, in 1993-1996 and 2002-2005 and from UK in 1991-1992. One locus, at ALAD on chromosome 9, showed consistent association with blood lead across countries and evidence for multiple independent allelic effects. The most significant single nucleotide polymorphism (SNP), rs1805313 (P = 3.91 × 10(-14) for lead concentration in a meta-analysis of all data), is known to have effects on ALAD expression in blood cells but other SNPs affecting ALAD expression did not affect blood lead. Variants at 12 other loci, including ABO, showed suggestive associations (5 × 10(-6) > P > 5 × 10(-8)). Identification of genetic polymorphisms affecting blood lead reinforces the view that genetic factors, as well as environmental ones, are important in determining blood lead levels. The ways in which ALAD variation affects lead uptake or distribution are still to be determined.
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.affiliation: QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: Veronica
authors.initials: V
authors.lastname: Dy
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: Gibran
authors.initials: G
authors.lastname: Hemani
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia, MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: George
authors.initials: G
authors.lastname: Mcmahon
authors.affiliation: School of Social and Community Medicine and.
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Centre for Child and Adolescent Health, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Taylor
authors.affiliation: School of Social and Community Medicine and.
authors.forename: Jean
authors.initials: J
authors.lastname: Golding
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Centre for Child and Adolescent Health, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Steer
authors.affiliation: QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia, MRC Integrative Epidemiology Unit, School of Social and Community Medicine and.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: QIMR Berghofer Medical Research Institute, Locked Bag 2000, Royal Brisbane Hospital, Queensland 4029, Australia, John.Whitfield@qimrberghofer.edu.au.
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
mesh_terms: D000328:Adult; D001315:Australia; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007854:Lead / Q000097:blood*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D000623:Porphobilinogen Synthase / Q000235:genetics* / Q000378:metabolism; D006113:United Kingdom; D055815:Young Adult
chemical_list: D007854:Lead; D000623:Porphobilinogen Synthase
references.citation: Environ Health Perspect. 2007 Mar;115(3):483-92
references.pmid: 17431502
references.citation: Environ Health Perspect. 2002 Apr;110(4):325-9
references.pmid: 11940448
references.citation: J Toxicol Environ Health A. 2007 Dec;70(23):1986-94
references.pmid: 17966070
references.citation: N Engl J Med. 2003 Jan 23;348(4):277-86
references.pmid: 12540640
references.citation: N Engl J Med. 2003 Apr 17;348(16):1517-26
references.pmid: 12700371
references.citation: Arch Environ Health. 2003 Mar;58(3):184-7
references.pmid: 14535579
references.citation: Annu Rev Med. 2004;55:209-22
references.pmid: 14746518
references.citation: Environ Health Perspect. 2004 May;112(6):746-50
references.pmid: 15121519
references.citation: Circulation. 2004 Jun 29;109(25):3196-201
references.pmid: 15184277
references.citation: Toxicol Appl Pharmacol. 2004 Jul 15;198(2):86-94
references.pmid: 15236947
references.citation: Med J Aust. 1982 Dec 11-25;2(12):573-6
references.pmid: 7162444
references.citation: Am J Epidemiol. 1983 Mar;117(3):344-55
references.pmid: 6829562
references.citation: Ann N Y Acad Sci. 1987;514:41-7
references.pmid: 3327436
references.citation: N Engl J Med. 1992 Jul 16;327(3):151-6
references.pmid: 1608406
references.citation: Environ Res. 1994 Apr;65(1):42-55
references.pmid: 8162884
references.citation: JAMA. 1994 Jul 27;272(4):284-91
references.pmid: 8028141
references.citation: J Lab Clin Med. 1994 Aug;124(2):193-8
references.pmid: 8051482
references.citation: BMJ. 1994 Nov 5;309(6963):1189-97
references.pmid: 7987149
references.citation: Environ Res. 1995 Feb;68(2):82-90
references.pmid: 7601076
references.citation: Sci Total Environ. 1996 May 31;184(3):203-9
references.pmid: 8643956
references.citation: Am J Epidemiol. 2004 Dec 15;160(12):1184-93
references.pmid: 15583371
references.citation: Crit Rev Toxicol. 2006 Apr;36(4):359-85
references.pmid: 16809103
references.citation: Circulation. 2006 Sep 26;114(13):1388-94
references.pmid: 16982939
references.citation: Environ Health Perspect. 2006 Oct;114(10):1538-41
references.pmid: 17035139
references.citation: Environ Health Perspect. 2007 Jan;115(1):35-41
references.pmid: 17366816
references.citation: Environ Health Perspect. 2007 Mar;115(3):451-4
references.pmid: 17431498
references.citation: Environ Health Perspect. 2007 Mar;115(3):472-82
references.pmid: 17431501
references.citation: PLoS Biol. 2008 May 6;6(5):e107
references.pmid: 18462017
references.citation: Eye (Lond). 2008 Jun;22(6):768-76
references.pmid: 17491602
references.citation: PLoS Genet. 2008 Jul;4(7):e1000118
references.pmid: 18604267
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373
references.citation: Am J Hum Genet. 2009 Nov;85(5):750-5
references.pmid: 19896111
references.citation: Environ Health Perspect. 2010 Jun;118(6):776-82
references.pmid: 20053595
references.citation: Am J Hum Genet. 2010 Jul 9;87(1):139-45
references.pmid: 20598278
references.citation: Bioinformatics. 2010 Sep 1;26(17):2190-1
references.pmid: 20616382
references.citation: Bioinformatics. 2010 Sep 15;26(18):2336-7
references.pmid: 20634204
references.citation: Nat Rev Genet. 2010 Jul;11(7):499-511
references.pmid: 20517342
references.citation: Biol Psychiatry. 2011 Sep 15;70(6):513-8
references.pmid: 21529783
references.citation: Nat Methods. 2012 Feb;9(2):179-81
references.pmid: 22138821
references.citation: Int J Epidemiol. 2013 Feb;42(1):97-110
references.pmid: 22507742
references.citation: Int J Epidemiol. 2013 Feb;42(1):111-27
references.pmid: 22507743
references.citation: Hum Mol Genet. 2013 Sep 15;22(18):3807-17
references.pmid: 23704328
references.citation: PLoS One. 2013;8(9):e72371
references.pmid: 24039753
references.citation: Nat Genet. 2013 Oct;45(10):1238-43
references.pmid: 24013639
references.citation: Curr Top Membr. 2014;73:321-55
references.pmid: 24745988
references.citation: PLoS One. 2014;9(6):e99269
references.pmid: 24940735
references.citation: Arch Intern Med. 2002 Nov 25;162(21):2443-9
references.pmid: 12437403
references.citation: Am J Ind Med. 2000 Sep;38(3):300-9
references.pmid: 10940968
references.citation: Environ Health Perspect. 2000 Oct;108(10):949-54
references.pmid: 11049814
references.citation: Environ Health Perspect. 2000 Aug;108(8):719-22
references.pmid: 10964791
references.citation: Am J Epidemiol. 2001 Jul 1;154(1):1-13
references.pmid: 11427399
references.citation: Int J Occup Med Environ Health. 2001;14(3):219-22
references.pmid: 11764848
references.citation: Nat Genet. 2002 Jan;30(1):97-101
references.pmid: 11731797
references.citation: Environ Health Perspect. 2007 Aug;115(8):1224-30
references.pmid: 17687451