title: Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.
abstract: The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
authors.affiliation: Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Buyske
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Cara L
authors.initials: CL
authors.lastname: Carty
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.forename: Logan
authors.initials: L
authors.lastname: Dumitrescu
authors.forename: Lucia A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mitchell
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Ambite
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Petra
authors.initials: P
authors.lastname: Buzkova
authors.forename: Chris S
authors.initials: CS
authors.lastname: Carlson
authors.forename: Barbara
authors.initials: B
authors.lastname: Cochran
authors.forename: David
authors.initials: D
authors.lastname: Duggan
authors.forename: Charles B
authors.initials: CB
authors.lastname: Eaton
authors.forename: Megan D
authors.initials: MD
authors.lastname: Fesinmeyer
authors.forename: Nora
authors.initials: N
authors.lastname: Franceschini
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Haessler
authors.forename: Nancy
authors.initials: N
authors.lastname: Jenny
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Tara C
authors.initials: TC
authors.lastname: Matise
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Robinson
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.forename: Alicia
authors.initials: A
authors.lastname: Young
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.forename: Dana C
authors.initials: DC
authors.lastname: Crawford
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
mesh_terms: D001741:Black or African American / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000208:ethnology / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008659:Metabolic Diseases / Q000208:ethnology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL