Fine-mapping in African Americans of 8 recently discovered genetic loci for plasma lipids: the Jackson Heart Study.
BACKGROUND
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear.


RESULTS
We genotyped 8 index single nucleotide polymorphisms (SNPs) and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared with the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, 2 with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African linkage disequilibrium patterns did not assist in narrowing association signals.


CONCLUSIONS
We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.
Keebler
Mary E
ME
Massachusetts General Hospital, Boston, MA 02115, USA.
Deo
Rahul C
RC
Surti
Aarti
A
Konieczkowski
David
D
Guiducci
Candace
C
Burtt
Noel
N
Buxbaum
Sarah G
SG
Sarpong
Daniel F
DF
Steffes
Michael W
MW
Wilson
James G
JG
Taylor
Herman A
HA
Kathiresan
Sekar
S
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D002874:Chromosome Mapping / Q000379:methods*; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D050356:Lipid Metabolism / Q000235:genetics*; D052439:Lipid Metabolism Disorders / Q000208:ethnology / Q000235:genetics; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D008055:Lipids