Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

G Davies; N. Armstrong; J. C. Bis; J. Bressler; V. Chouraki; S. Giddaluru; E. Hofer; C. A. Ibrahim-Verbaas; M. Kirin; J. Lahti; S. J. van der Lee; S. Le Hellard; T. Liu; R E Marioni; C. Oldmeadow; I. Postmus; A V Smith; J. A. Smith; A. Thalamuthu; R. Thomson; V Vitart; J. Wang; L Yu; L Zgaga; W. Zhao; R. Boxall; S E Harris; W D Hill; D C Liewald; M Luciano; H. Adams; D. Ames; N. Amin; P. Amouyel; A. A. Assareh; R Au; J T Becker; A Beiser; C Berr; L Bertram; E Boerwinkle; B M Buckley; H. Campbell; J. Corley; P L De Jager; C Dufouil; J G Eriksson; T Espeseth; J D Faul; I Ford; Generation Scotland; R F Gottesman; M E Griswold; V Gudnason; T B Harris; G Heiss; A Hofman; E G Holliday; J Huffman; S L R Kardia; N Kochan; D S Knopman; J B Kwok; J-C Lambert; T Lee; G Li; S-C Li; M Loitfelder; O L Lopez; A J Lundervold; A Lundqvist; K A Mather; S S Mirza; L Nyberg; B A Oostra; A Palotie; G Papenberg; A. Pattie; K Petrovic; O. Polasek; B M Psaty; P. Redmond; S Reppermund; J I Rotter; H Schmidt; M Schuur; P W Schofield; R J Scott; V M Steen; D J Stott; J C van Swieten; K. D. Taylor; J Trollor; S Trompet; A G Uitterlinden; G Weinstein; E Widen; B G Windham; J W Jukema; A. F. Wright; M J Wright; Q Yang; H Amieva; J R Attia; D. A. Bennett; H Brodaty; A J M de Craen; C. Hayward; M A Ikram; U Lindenberger; L-S Nilsson; D J Porteous; K Räikkönen; I Reinvang; I Rudan; P S Sachdev; R Schmidt; P R Schofield; V Srikanth; J M Starr; S T Turner; D R Weir; J F Wilson; C van Duijn; L Launer; A L Fitzpatrick; S Seshadri; T H Mosley Jr; I J Deary

doi:10.1038/mp.2014.188

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

G Davies, N. Armstrong, J. C. Bis, J. Bressler, V. Chouraki, S. Giddaluru, E. Hofer, C. A. Ibrahim-Verbaas, M. Kirin, J. Lahti, S. J. van der Lee, S. Le Hellard, T. Liu, R E Marioni, C. Oldmeadow, I. Postmus, A V Smith, J. A. Smith, A. Thalamuthu, R. ThomsonV Vitart, J. Wang, L Yu, L Zgaga, W. Zhao, R. Boxall, S E Harris, W D Hill, D C Liewald, M Luciano, H. Adams, D. Ames, N. Amin, P. Amouyel, A. A. Assareh, R Au, J T Becker, A Beiser, C Berr, L Bertram, E Boerwinkle, B M Buckley, H. Campbell, J. Corley, P L De Jager, C Dufouil, J G Eriksson, T Espeseth, J D Faul, I Ford, Generation Scotland, R F Gottesman, M E Griswold, V Gudnason, T B Harris, G Heiss, A Hofman, E G Holliday, J Huffman, S L R Kardia, N Kochan, D S Knopman, J B Kwok, J-C Lambert, T Lee, G Li, S-C Li, M Loitfelder, O L Lopez, A J Lundervold, A Lundqvist, K A Mather, S S Mirza, L Nyberg, B A Oostra, A Palotie, G Papenberg, A. Pattie, K Petrovic, O. Polasek, B M Psaty, P. Redmond, S Reppermund, J I Rotter, H Schmidt, M Schuur, P W Schofield, R J Scott, V M Steen, D J Stott, J C van Swieten, K. D. Taylor, J Trollor, S Trompet, A G Uitterlinden, G Weinstein, E Widen, B G Windham, J W Jukema, A. F. Wright, M J Wright, Q Yang, H Amieva, J R Attia, D. A. Bennett, H Brodaty, A J M de Craen, C. Hayward, M A Ikram, U Lindenberger, L-S Nilsson, D J Porteous, K Räikkönen, I Reinvang, I Rudan, P S Sachdev, R Schmidt, P R Schofield, V Srikanth, J M Starr, S T Turner, D R Weir, J F Wilson, C van Duijn, L Launer, A L Fitzpatrick, S Seshadri, T H Mosley Jr, I J Deary

Research output: Contribution to journal › Article › peer-review

Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10⁻⁹, MIR2113; rs17522122, P=2.55 × 10⁻⁸, AKAP6; rs10119, P=5.67 × 10⁻⁹, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10⁻¹⁷). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

Original language	English
Pages (from-to)	183-192
Number of pages	10
Journal	Molecular Psychiatry
Volume	20
Issue number	2
Early online date	3 Feb 2015
DOIs	https://doi.org/10.1038/mp.2014.188
Publication status	Published - 28 Feb 2015

Keywords / Materials (for Non-textual outputs)

CPG-BINDING PROTEIN-2
ALZHEIMERS-DISEASE
HUMAN INTELLIGENCE
APOLIPOPROTEIN-E
OLD-AGE
SUSCEPTIBILITY LOCI
IDENTIFIES VARIANTS
TEST BATTERIES
TYPE-4 ALLELE
HUMAN HEIGHT

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Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
A Hundred at Ninety: the common cause Hypothesis of Ageing tested in four waves of the Lothian Birth Cohort 1921
Deary, I., Bates, T., Gow, A. & Starr, J.
UK central government bodies/local authorities, health and hospital authorities
1/01/11 → 31/12/12
Project: Research

Gail Davies
- gail.daviesed.acuk
- School of Philosophy, Psychology and Language Sciences - Senior Research Fellow
- Edinburgh Neuroscience
Person: Academic: Research Active (Research Assistant)

Cite this

Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C. A., Kirin, M., Lahti, J., van der Lee, S. J., Le Hellard, S., Liu, T., Marioni, R. E., Oldmeadow, C., Postmus, I., Smith, A. V., Smith, J. A., Thalamuthu, A., ... Deary, I. J. (2015). Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949). Molecular Psychiatry, 20(2), 183-192. https://doi.org/10.1038/mp.2014.188

@article{c124f5d4c1ca47e2a1422f2d5a0112f9,

title = "Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)",

abstract = "General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer{\textquoteright}s disease: TOMM40, APOE, ABCG1 and MEF2C.",

keywords = "CPG-BINDING PROTEIN-2, ALZHEIMERS-DISEASE, HUMAN INTELLIGENCE, APOLIPOPROTEIN-E, OLD-AGE, SUSCEPTIBILITY LOCI, IDENTIFIES VARIANTS, TEST BATTERIES, TYPE-4 ALLELE, HUMAN HEIGHT",

author = "G Davies and N. Armstrong and Bis, {J. C.} and J. Bressler and V. Chouraki and S. Giddaluru and E. Hofer and Ibrahim-Verbaas, {C. A.} and M. Kirin and J. Lahti and {van der Lee}, {S. J.} and {Le Hellard}, S. and T. Liu and Marioni, {R E} and C. Oldmeadow and I. Postmus and Smith, {A V} and Smith, {J. A.} and A. Thalamuthu and R. Thomson and V Vitart and J. Wang and L Yu and L Zgaga and W. Zhao and R. Boxall and Harris, {S E} and Hill, {W D} and Liewald, {D C} and M Luciano and H. Adams and D. Ames and N. Amin and P. Amouyel and Assareh, {A. A.} and R Au and Becker, {J T} and A Beiser and C Berr and L Bertram and E Boerwinkle and Buckley, {B M} and H. Campbell and J. Corley and {De Jager}, {P L} and C Dufouil and Eriksson, {J G} and T Espeseth and Faul, {J D} and I Ford and {Generation Scotland} and Gottesman, {R F} and Griswold, {M E} and V Gudnason and Harris, {T B} and G Heiss and A Hofman and Holliday, {E G} and J Huffman and Kardia, {S L R} and N Kochan and Knopman, {D S} and Kwok, {J B} and J-C Lambert and T Lee and G Li and S-C Li and M Loitfelder and Lopez, {O L} and Lundervold, {A J} and A Lundqvist and Mather, {K A} and Mirza, {S S} and L Nyberg and Oostra, {B A} and A Palotie and G Papenberg and A. Pattie and K Petrovic and O. Polasek and Psaty, {B M} and P. Redmond and S Reppermund and Rotter, {J I} and H Schmidt and M Schuur and Schofield, {P W} and Scott, {R J} and Steen, {V M} and Stott, {D J} and {van Swieten}, {J C} and Taylor, {K. D.} and J Trollor and S Trompet and Uitterlinden, {A G} and G Weinstein and E Widen and Windham, {B G} and Jukema, {J W} and Wright, {A. F.} and Wright, {M J} and Q Yang and H Amieva and Attia, {J R} and Bennett, {D. A.} and H Brodaty and {de Craen}, {A J M} and C. Hayward and Ikram, {M A} and U Lindenberger and L-S Nilsson and Porteous, {D J} and K R{\"a}ikk{\"o}nen and I Reinvang and I Rudan and Sachdev, {P S} and R Schmidt and Schofield, {P R} and V Srikanth and Starr, {J M} and Turner, {S T} and Weir, {D R} and Wilson, {J F} and Duijn, {C van} and L Launer and Fitzpatrick, {A L} and S Seshadri and {Mosley Jr}, {T H} and Deary, {I J}",

year = "2015",

month = feb,

day = "28",

doi = "10.1038/mp.2014.188",

language = "English",

volume = "20",

pages = "183--192",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "2",

}

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H , Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, Wright, AF, Wright, MJ, Yang, Q, Amieva, H, Attia, JR, Bennett, DA, Brodaty, H, de Craen, AJM, Hayward, C, Ikram, MA, Lindenberger, U, Nilsson, L-S, Porteous, DJ, Räikkönen, K, Reinvang, I, Rudan, I, Sachdev, PS, Schmidt, R, Schofield, PR, Srikanth, V, Starr, JM, Turner, ST, Weir, DR, Wilson, JF, Duijn, CV, Launer, L, Fitzpatrick, AL, Seshadri, S, Mosley Jr, TH & Deary, IJ 2015, 'Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)', Molecular Psychiatry, vol. 20, no. 2, pp. 183-192. https://doi.org/10.1038/mp.2014.188

TY - JOUR

T1 - Genetic contributions to variation in general cognitive function

T2 - a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

AU - Davies, G

AU - Armstrong, N.

AU - Bis, J. C.

AU - Bressler, J.

AU - Chouraki, V.

AU - Giddaluru, S.

AU - Hofer, E.

AU - Ibrahim-Verbaas, C. A.

AU - Kirin, M.

AU - Lahti, J.

AU - van der Lee, S. J.

AU - Le Hellard, S.

AU - Liu, T.

AU - Marioni, R E

AU - Oldmeadow, C.

AU - Postmus, I.

AU - Smith, A V

AU - Smith, J. A.

AU - Thalamuthu, A.

AU - Thomson, R.

AU - Vitart, V

AU - Wang, J.

AU - Yu, L

AU - Zgaga, L

AU - Zhao, W.

AU - Boxall, R.

AU - Harris, S E

AU - Hill, W D

AU - Liewald, D C

AU - Luciano, M

AU - Adams, H.

AU - Ames, D.

AU - Amin, N.

AU - Amouyel, P.

AU - Assareh, A. A.

AU - Au, R

AU - Becker, J T

AU - Beiser, A

AU - Berr, C

AU - Bertram, L

AU - Boerwinkle, E

AU - Buckley, B M

AU - Campbell, H.

AU - Corley, J.

AU - De Jager, P L

AU - Dufouil, C

AU - Eriksson, J G

AU - Espeseth, T

AU - Faul, J D

AU - Ford, I

AU - Generation Scotland

AU - Gottesman, R F

AU - Griswold, M E

AU - Gudnason, V

AU - Harris, T B

AU - Heiss, G

AU - Hofman, A

AU - Holliday, E G

AU - Huffman, J

AU - Kardia, S L R

AU - Kochan, N

AU - Knopman, D S

AU - Kwok, J B

AU - Lambert, J-C

AU - Lee, T

AU - Li, G

AU - Li, S-C

AU - Loitfelder, M

AU - Lopez, O L

AU - Lundervold, A J

AU - Lundqvist, A

AU - Mather, K A

AU - Mirza, S S

AU - Nyberg, L

AU - Oostra, B A

AU - Palotie, A

AU - Papenberg, G

AU - Pattie, A.

AU - Petrovic, K

AU - Polasek, O.

AU - Psaty, B M

AU - Redmond, P.

AU - Reppermund, S

AU - Rotter, J I

AU - Schmidt, H

AU - Schuur, M

AU - Schofield, P W

AU - Scott, R J

AU - Steen, V M

AU - Stott, D J

AU - van Swieten, J C

AU - Taylor, K. D.

AU - Trollor, J

AU - Trompet, S

AU - Uitterlinden, A G

AU - Weinstein, G

AU - Widen, E

AU - Windham, B G

AU - Jukema, J W

AU - Wright, A. F.

AU - Wright, M J

AU - Yang, Q

AU - Amieva, H

AU - Attia, J R

AU - Bennett, D. A.

AU - Brodaty, H

AU - de Craen, A J M

AU - Hayward, C.

AU - Ikram, M A

AU - Lindenberger, U

AU - Nilsson, L-S

AU - Porteous, D J

AU - Räikkönen, K

AU - Reinvang, I

AU - Rudan, I

AU - Sachdev, P S

AU - Schmidt, R

AU - Schofield, P R

AU - Srikanth, V

AU - Starr, J M

AU - Turner, S T

AU - Weir, D R

AU - Wilson, J F

AU - Duijn, C van

AU - Launer, L

AU - Fitzpatrick, A L

AU - Seshadri, S

AU - Mosley Jr, T H

AU - Deary, I J

PY - 2015/2/28

Y1 - 2015/2/28

N2 - General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

AB - General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

KW - CPG-BINDING PROTEIN-2

KW - ALZHEIMERS-DISEASE

KW - HUMAN INTELLIGENCE

KW - APOLIPOPROTEIN-E

KW - OLD-AGE

KW - SUSCEPTIBILITY LOCI

KW - IDENTIFIES VARIANTS

KW - TEST BATTERIES

KW - TYPE-4 ALLELE

KW - HUMAN HEIGHT

U2 - 10.1038/mp.2014.188

DO - 10.1038/mp.2014.188

M3 - Article

SN - 1359-4184

VL - 20

SP - 183

EP - 192

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 2

ER -

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

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Keywords / Materials (for Non-textual outputs)

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Projects

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

A Hundred at Ninety: the common cause Hypothesis of Ageing tested in four waves of the Lothian Birth Cohort 1921

Profiles

Gail Davies

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