Abstract P103: Genetic Analysis of Admixed US Populations Identifies Associations with Mean Corpuscular Volume
Authors: Hodonsky Chani J , Nishimura Katherine K , Tao Ran , Buyske Steve , Fornage Myriam , Hindorff Lucia A , Kocarnik Jonathan , Li Yun , Lin Danyu , Loos Ruth J , Tang Weihong , Thyagarajan Bharat , Wassel Christina L , Reiner Alex P , North Kari E , Kooperberg Charles L , Avery Christy L 
Published: March 2022

Introduction:
Mean corpuscular volume (MCV) of red blood cells (RBCs) is a heritable index commonly used in clinical workup of anemia. Macrocytosis, or high MCV, is associated with cardiovascular events in chronic kidney disease patients and all-cause mortality. Genome-wide association studies (GWAS) of MCV have been conducted primarily in European and Asian populations; few have included populations of African or American ancestry. The Multiethnic Genotyping Array (MEGA) was designed to improve variant discovery and fine-mapping in US minorities by better capturing population-specific genetic variation. To identify novel MCV loci and examine evidence of generalization of previously reported MCV loci to populations with African and Amerindian genetic admixture, we conducted a GWAS of African American and Hispanic/Latino Population Architecture using Genomics and Epidemiology (PAGE II) participants on the MEGA array.

Methods:
We employed Illumina MEGA genotype data to evaluate the association between ~1.5 million SNPs and MCV. Generalized estimating equation models were adjusted for age, sex, current smoking status, study, study center, and the top 10 study-specific principal components of genetic ancestry. Race/ethnic-stratified analyses were combined using inverse-variance weighted fixed-effects meta-analysis to evaluate the entire study sample. Significance thresholds of 1.8x10
-3
and 5x10
-8
were used to define generalization and genome-wide significance, respectively.

Results:
The study population of 3,734 African Americans and 15,505 Hispanic/Latinos was 62% female with a mean age of 50 (range: 18 to 94 years); 19% of participants were current smokers. Trans-ethnic meta-analysis identified 12 genome-wide significant loci for MCV, including two associations at previously unreported loci:
FIGNL1/IKZF1
(chromosome 7p12.2, coded allele frequency [CAF] range=51 to 57%), and
LRP6
(chromosome 12p13.2, CAF range=0.3 to 1.7%). FIGNL1 is involved in DNA double-strand-break repair, and IKZF1 is a zinc-finger protein that functions in the hemo-lymphopoetic system.
LRP6
encodes an LDL receptor involved in the Wnt/beta-catenin signaling cascade. Ninety-three percent of previously reported MCV loci generalized to the combined PAGE study population, ten at genome-wide significant levels. No previously unreported MCV loci were detected in race/ethnic stratified analyses.

Conclusion:
Generalization of previously reported MCV loci to African Americans and Hispanic/Latinos highlights the shared genetic architecture of MCV. The potentially novel associations identified at chromosomes 7p12.2 and 12p13.2 also underscore the benefits of performing GWAS in ancestrally diverse populations using arrays that better capture global genetic variation.