Abstract
Introduction:
MRI-defined brain infarcts (BI), most of which are small sub-cortical brain infarcts (SSBI), are highly prevalent in older persons. Most BI are covert, which is not associated with clinically overt stroke. Nonetheless, they are powerful predictors of future risk for stroke, cognitive decline, and dementia. Little is known about the genetic determinants of BI.
Methods:
We performed a trans-ethnic meta-analysis of GWAS of MRI-defined BI and SSBI in 20,949 participants belonging to 5 ethnic groups: Europeans, African-Americans, Hispanic-Americans, Malays, and Chinese. A total of 23 population-based studies from the CHARGE consortium participated in this effort, comprising of 3,726 cases and 17,223 controls for BI, 2,112 cases and 15,432 controls for SSBI. GWAS based on imputed genotypes using the 1000 Genomes phase 1, version 3 panel was performed in each study [using logistic regression]. Meta-analysis of association statistics was performed using a Bayesian partition model (MANTRA); secondary analyses used fixed effect (FE) inverse variance weighting. Loci with log
10
[Bayesian factor (BF)]>5 were considered genome-wide significant and loci with log
10
[BF]>4.5 and mean imputation accuracy score >0.80 were chosen for replication.
Results:
33 variants (3 loci) reached genome-wide significance, in association with BI, on chromosome: 13q12 (Index SNP: log
10
[BF]=7, P
FE
=5.8х10
-9
, OR
FE
=1.2, minor allele frequency [MAF]=0.34), 5q23 (Index SNP: log
10
[BF]=6.5, P
FE
=1.8х10
-8
, OR
FE
=1.2, MAF=0.21) and 15q26 (Index SNP: log
10
[BF]=5.3, P
FE
=3.4х10
-7
, OR
FE
=1.8, MAF=0.03). These loci comprise genes involved in response to anti-hypertensive drugs, glucose transport, connective tissue assembly and synaptic transmission. Three additional loci showed suggestive associations (log
10
[BF] 4.5 to 5). Five of these six loci were associated with both BI and SSBI (Index SNP log
10
[BF]>2), but none reached genome-wide significance for SSBI.
Conclusion:
This large scale trans-ethnic GWAS meta-analysis identified three novel risk loci for MRI-defined BI. Replication analysis and functional validation are ongoing. These findings may provide novel insight into biological mechanisms underlying covert vascular brain injury