Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Tzourio C; Jimenez-Conde J; Psaty BM; Rice K; McWhirter R; Rothwell PM; Kwok JB; Rajan KB; Wittfeld K; van Duijn CM; Malik R; Amin N; Johnson JA; Windham BG; Chauhan G; Wong Q; Sachdev PS; Melander O; Pulit SL; Evans DA; Ikram MA; Wen W; Worrall BB; Mather KA; Starr JM; Hopewell JC; Benavente OR; Bevan S; Stott DJ; Aparicio HJ; Armstrong NJ; Seshadri S; Traylor M; Gottesman RF; Debette S; Stroke Genetics Network (SiGN); the International Stroke Genetics Consortium (ISGC); METASTROKE; Alzheimer's Disease Genetics Consortium (ADGC); and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; Mitchell BD; Ford I; Rotter JI; Asselbergs FW; van der Lugt A; Aggarwal NT; Lopez OL; DeStefano AL; Launer LJ; Schilling S; Zhu YC; Trompet S; DeCarli C; Teumer A; Hosten N; Cheng CY; Beekman M; Rexrode K; Adams HHH; Levi C; Muñoz Maniega S; Thalamuthu A; Longstreth WT Jr; Cole JW; von Sarnowski B; Hofer E; Sudlow CLM; Jern C; Völker U; van der Lee SJ; Kaffashian S; Deelen J; Uh HW; Sharma P; Slowik A; Ames D; Sargurupremraj M; Maillard P; Kjartansson O; Bis JC; Kato N; Boncoraglio GB; Beecham AH; Schofield PR; Wasssertheil-Smoller S; Uitterlinden AG; Brodaty H; Sacco RL; Luciano M; Rundek T; Takeuchi F; Arnett DK; Thijs V; Bastin ME; Mosley TH; Srikanth V; Blanton SH; Hilal S; Chouraki V; Liao J; Amouyel P; Woo D; Griswold ME; Lemmens R; Mazoyer B; McArdle PF; Schellenberg GD; Hernández MDCV; Chen C; Callisaya M; Jukema JW; Guðnason V; Nabika T; van der Grond J; Moran C; Ikram MK; Wright CB; Wong TY; Schmidt H; Yamaguchi S; Schmidt R; Knopman DS; Wright MJ; van der Graaf Y; Lee JM; Romero JR; De Jager PL; Liewald D; Smith AV; Beecham GW; Saba Y; Jian X; Grabe HJ; Markus HS; Dichgans M; Deary IJ; Phan T; Meschia JF; Rich SS; de Bakker PIW; Chong E; Slagboom PE; Hofman A; Geerlings MI; Grewal RP; Kittner SJ; Lindgren A; Thomson R; Rosand J; Montine TJ; Satizabal CL; Vernooij MW; Rutten-Jacobs LCA; Fornage M; Wardlaw JM

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Tzourio C; Jimenez-Conde J; Psaty BM; Rice K; McWhirter R; Rothwell PM; Kwok JB; Rajan KB; Wittfeld K; van Duijn CM; Malik R; Amin N; Johnson JA; Windham BG; Chauhan G; Wong Q; Sachdev PS; Melander O; Pulit SL; Evans DA; Ikram MA; Wen W; Worrall BB; Mather KA; Starr JM; Hopewell JC; Benavente OR; Bevan S; Stott DJ; Aparicio HJ; Armstrong NJ; Seshadri S; Traylor M; Gottesman RF; Debette S; Stroke Genetics Network (SiGN); the International Stroke Genetics Consortium (ISGC); METASTROKE; Alzheimer's Disease Genetics Consortium (ADGC); and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium; Mitchell BD; Ford I; Rotter JI; Asselbergs FW; van der Lugt A; Aggarwal NT; Lopez OL; DeStefano AL; Launer LJ; Schilling S; Zhu YC; Trompet S; DeCarli C; Teumer A; Hosten N; Cheng CY; Beekman M; Rexrode K; Adams HHH; Levi C; Muñoz Maniega S; Thalamuthu A; Longstreth WT Jr; Cole JW; von Sarnowski B; Hofer E; Sudlow CLM; Jern C; Völker U; van der Lee SJ; Kaffashian S; Deelen J; Uh HW; Sharma P; Slowik A; Ames D; Sargurupremraj M; Maillard P; Kjartansson O; Bis JC; Kato N; Boncoraglio GB; Beecham AH; Schofield PR; Wasssertheil-Smoller S; Uitterlinden AG; Brodaty H; Sacco RL; Luciano M; Rundek T; Takeuchi F; Arnett DK; Thijs V; Bastin ME; Mosley TH; Srikanth V; Blanton SH; Hilal S; Chouraki V; Liao J; Amouyel P; Woo D; Griswold ME; Lemmens R; Mazoyer B; McArdle PF; Schellenberg GD; Hernández MDCV; Chen C; Callisaya M; Jukema JW; Guðnason V; Nabika T; van der Grond J; Moran C; Ikram MK; Wright CB; Wong TY; Schmidt H; Yamaguchi S; Schmidt R; Knopman DS; Wright MJ; van der Graaf Y; Lee JM; Romero JR; De Jager PL; Liewald D; Smith AV; Beecham GW; Saba Y; Jian X; Grabe HJ; Markus HS; Dichgans M; Deary IJ; Phan T; Meschia JF; Rich SS; de Bakker PIW; Chong E; Slagboom PE; Hofman A; Geerlings MI; Grewal RP; Kittner SJ; Lindgren A; Thomson R; Rosand J; Montine TJ; Satizabal CL; Vernooij MW; Rutten-Jacobs LCA; Fornage M; Wardlaw JM

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Tzourio C

Jimenez-Conde J

Psaty BM

Rice K

McWhirter R

Rothwell PM

Kwok JB

Rajan KB

Wittfeld K

van Duijn CM

Malik R

Amin N

Johnson JA

Windham BG

Chauhan G

Wong Q

Sachdev PS

Melander O

Pulit SL

Evans DA

Ikram MA

Wen W

Worrall BB

Mather KA

Starr JM

Hopewell JC

Benavente OR

Bevan S

Stott DJ

Aparicio HJ

Armstrong NJ

Seshadri S

Traylor M

Gottesman RF

Debette S; Stroke Genetics Network (SiGN); the International Stroke Genetics Consortium (ISGC); METASTROKE; Alzheimer's Disease Genetics Consortium (ADGC); and the Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Mitchell BD

Ford I

Rotter JI

Asselbergs FW

van der Lugt A

Aggarwal NT

Lopez OL

DeStefano AL

Launer LJ

Schilling S

Zhu YC

Trompet S

DeCarli C

Teumer A

Hosten N

Cheng CY

Beekman M

Rexrode K

Adams HHH

Levi C

Muñoz Maniega S

Thalamuthu A

Longstreth WT Jr

Cole JW

von Sarnowski B

Hofer E

Sudlow CLM

Jern C

Völker U

van der Lee SJ

Kaffashian S

Deelen J

Uh HW

Sharma P

Slowik A

Ames D

Sargurupremraj M

Maillard P

Kjartansson O

Bis JC

Kato N

Boncoraglio GB

Beecham AH

Schofield PR

Wasssertheil-Smoller S

Uitterlinden AG

Brodaty H

Sacco RL

Luciano M

Rundek T

Takeuchi F

Arnett DK

Thijs V

Bastin ME

Mosley TH

Srikanth V

Blanton SH

Hilal S

Chouraki V

Liao J

Amouyel P

Woo D

Griswold ME

Lemmens R

Mazoyer B

McArdle PF

Schellenberg GD

Hernández MDCV

Chen C

Callisaya M

Jukema JW

Guðnason V

Nabika T

van der Grond J

Moran C

Ikram MK

Wright CB

Wong TY

Schmidt H

Yamaguchi S

Schmidt R

Knopman DS

Wright MJ

van der Graaf Y

Lee JM

Romero JR

De Jager PL

Liewald D

Smith AV

Beecham GW

Saba Y

Jian X

Grabe HJ

Markus HS

Dichgans M

Deary IJ

Phan T

Meschia JF

Rich SS

de Bakker PIW

Chong E

Slagboom PE

Hofman A

Geerlings MI

Grewal RP

Kittner SJ

Lindgren A

Thomson R

Rosand J

Montine TJ

Satizabal CL

Vernooij MW

Rutten-Jacobs LCA

Fornage M

Wardlaw JM

Katso/Avaa

Publisher's version (287Kb)

Lataukset:

doi:10.1212/WNL.0000000000006851

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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021042827362

Tiivistelmä

OBJECTIVE:

To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.

METHODS:

We
performed meta-analyses of genome-wide association studies (GWAS) and
examined associations of vascular risk factors and their genetic risk
scores (GRS) with MRI-defined BI and a subset of BI, namely, small
subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5
ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up
in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with
SBBI), and we tested associations with related phenotypes including
ischemic stroke and pathologically defined BI.

RESULTS:

The
mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising
after age 65. Two loci showed genome-wide significant association with
BI: FBN2, p = 1.77 × 10^-8; and LINC00539/ZDHHC20, p = 5.82 × 10^-9.
Both have been associated with blood pressure (BP)-related phenotypes,
but did not replicate in the smaller follow-up sample or show
associations with related phenotypes. Age- and sex-adjusted associations
with BI and SSBI were observed for BP traits (p value for BI, p _[BI] = 9.38 × 10^-25; p _[SSBI] = 5.23 × 10^-14 for hypertension), smoking (p _[BI] = 4.4 × 10^-10; p _[SSBI] = 1.2 × 10^-4), diabetes (p _[BI] = 1.7 × 10^-8; p _[SSBI] = 2.8 × 10^-3), previous cardiovascular disease (p _[BI] = 1.0 × 10^-18; p _[SSBI] = 2.3 × 10^-7), stroke (p _[BI] = 3.9 × 10^-69; p _[SSBI] = 3.2 × 10^-24), and MRI-defined white matter hyperintensity burden (p _[BI] = 1.43 × 10^-157; p _[SSBI] = 3.16 × 10^-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.

CONCLUSION:

In
this multiethnic GWAS meta-analysis, including over 20,000
population-based participants, we identified genetic risk loci for BI
requiring validation once additional large datasets become available.
High BP, including genetically determined, was the most significant
modifiable, causal risk factor for BI.

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