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

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

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

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

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

Chauhan G

Adams HHH

Satizabal CL

Bis JC

Teumer A

Sargurupremraj M

Hofer E

Trompet S

Hilal S

Smith AV

Jian X

Malik R

Traylor M

Pulit SL

Amouyel P

Mazoyer B

Zhu YC

Kaffashian S

Schilling S

Beecham GW

Montine TJ

Schellenberg GD

Kjartansson O

Guðnason V

Knopman DS

Griswold ME

Windham BG

Gottesman RF

Mosley TH

Schmidt R

Saba Y

Schmidt H

Takeuchi F

Yamaguchi S

Nabika T

Kato N

Rajan KB

Aggarwal NT

De Jager PL

Evans DA

Psaty BM

Rotter JI

Rice K

Lopez OL

Liao J

Chen C

Cheng CY

Wong TY

Ikram MK

van der Lee SJ

Amin N

Chouraki V

DeStefano AL

Aparicio HJ

Romero JR

Maillard P

DeCarli C

Wardlaw JM

Hernández MDCV

Luciano M

Liewald D

Deary IJ

Starr JM

Bastin ME

Muñoz Maniega S

Slagboom PE

Beekman M

Deelen J

Uh HW

Lemmens R

Brodaty H

Wright MJ

Ames D

Boncoraglio GB

Hopewell JC

Beecham AH

Blanton SH

Wright CB

Sacco RL

Wen W

Thalamuthu A

Armstrong NJ

Chong E

Schofield PR

Kwok JB

van der Grond J

Stott DJ

Ford I

Jukema JW

Vernooij MW

Hofman A

Uitterlinden AG

van der Lugt A

Wittfeld K

Grabe HJ

Hosten N

von Sarnowski B

Völker U

Levi C

Jimenez-Conde J

Sharma P

Sudlow CLM

Rosand J

Woo D

Cole JW

Meschia JF

Slowik A

Thijs V

Lindgren A

Melander O

Grewal RP

Rundek T

Rexrode K

Rothwell PM

Arnett DK

Jern C

Johnson JA

Benavente OR

Wasssertheil-Smoller S

Lee JM

Wong Q

Mitchell BD

Rich SS

McArdle PF

Geerlings MI

van der Graaf Y

de Bakker PIW

Asselbergs FW

Srikanth V

Thomson R

McWhirter R

Moran C

Callisaya M

Phan T

Rutten-Jacobs LCA

Bevan S

Tzourio C

Mather KA

Sachdev PS

van Duijn CM

Worrall BB

Dichgans M

Kittner SJ

Markus HS

Ikram MA

Fornage M

Launer LJ

Seshadri S

Longstreth WT Jr

Debette S

Stroke Genetics Network (SiGN)

International Stroke Genetics Consortium (ISGC)

METASTROKE

Alzheimer's Disease Genetics Consortium (ADGC)

Neurology Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)

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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