Abstract MP068: Association Study of SNPs and measures of adiposity among 51990 European and European American Identifies Three Novel Loci
Authors: Yoneyama Sachiko , Taylor Kira C , Fox Caroline S , Keating Brendan J , Gong Yan , Reiner Alexander P , Shen Haiqing , Gorski Mathias , Padmanabhan Sandosh , Rafelt Suzanne , Munroe Patricia , Lanktree Matthew , Johnson Toby , Gaunt Tom R , Guo Yiran , Speilotes Liz , Redline Susan , Burke Gregory , Taylor Herman , Ordovas Jose , Jaquish Cashell , Heard-Costa Nancy ,   the CARe IBC Consortium, North Kari E , Demerath Ellen W 
Published: July 2021

Introduction and objectives.
Measures of adiposity such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with adverse cardiovascular events and diabetes independent of body mass index (BMI). WC and WHR have high heritability and multiple susceptibility loci have been identified across the genome, including
GRB14
,
LYPAL1
, and
VEGFA
. We aim to identify novel loci associated with WC and WHR using a bespoke SNP array focused on cardio-centric candidate genes.

Methods.
We assessed the association between SNPs and anthropometry phenotypes WC adjusted for BMI (cm), and WHR adjusted for BMI among 51990 individuals of European ancestry from NHLBI’s Candidate Gene Association Resource (CARe) project and 14 other cohorts. The study population consisted of women and men aged 20 to 80, of which 65% were females. Individuals were genotyped using the ITMAT/Broad/CARE (IBC) chip, which includes ∼50,000 densely mapped cosmopolitan tagged SNPs across ∼2100 candidate genes. We modeled each trait as a function of age, study site, and ancestry, and conducted a fixed-effects meta-analysis.

Results.
Three novel loci reached our Bonferroni adjusted threshold for statistical significance (P<2E-6). The A allele of SNP
rs761422
in gene
MFAP2
was associated with decreased WC adjusted for BMI (P=4.4E-7), and has previously been reported in a height GWAS. The C allele of SNP rs2811337 near
TMCC1
, involved in signaling pathways, and the A allele of SNP rs7302703 in gene
HOXC10
, involved in cell differentiation, were associated with decreased WHR adjusted for BMI (P=8.6E-9 and P=2.8E-7, respectively). Fourteen loci have been previously reported in association with WHR adjusted for BMI, five of which, were included on the IBC chip. Of the five, three also reached statistical significance with the same direction of effect in our sample:
RSPO3
(P=3.0E-10),
ADAMTS9
(P=8.6E-9),and
ITPR2
(P=5.6E-8). All SNPs were common variants (MAF>10%). Fine mapping is currently underway to determine whether each locus may contain multiple independent signals. Replication cohorts have been identified and we are working to verify the novel loci and investigate sub-significant loci.

Conclusions
. In 51990 European decent individuals typed on a dense IBC chip, we identified 3 novel loci and replicated 3 additional loci. Significant loci among WC adjusted for BMI, and WHR adjusted for BMI were distinct from one another, indicating each measure of adiposity may be capturing distinct underlying phenotypes and thus different pathways through which risk alleles affect adiposity. We will pursue further assessment of risk loci and adiposity through fine mapping and follow-up genotyping.