Abstract 46: Whole Genome Sequence Analysis Of Blood Pressure Phenotypes In The Trans-omics For Precision Medicine And Centers For Common Disease Genomics Programs
Authors: Kelly Tanika N , Sun Xiao , Brody Jennifer A , Gagliano Sarah A , He Karen Y , Hellwege Jacklyn N ,   TOPMed Blood Pressure Working Group
Published: March 2020

Background:
Although genome-wide association studies (GWAS) have made important strides in localizing genomic regions associated with blood pressure (BP) phenotypes, the causal mechanisms underlying the vast majority of identified signals remain to be elucidated. Whole genome sequencing (WGS) provides an opportunity for novel genomic discoveries and high-resolution refinement of identified GWAS signals.

Methods:
This multi-stage genomic study of BP was conducted in an ancestrally diverse sample of up to 735,905 participants from 20 cohorts. In the discovery stage WGS study, variants with minor allele counts >10 were tested for association with systolic BP (SBP), diastolic BP (DBP), and hypertension (HTN) among 50,755 participants from the Trans-Omics for Precision Medicine and Centers for Common Disease Genomics programs using the Analysis Commons cloud based platform. Variants achieving suggestive genome-wide significance (P<1х10
-6
) were tested for replication among UK Biobank (N=383,145) and Million Veterans Program (N=318,891) participants with GWAS data imputed to the TOPMed and 1000 Genomes reference panels, respectively.

Results:
Discovery stage analyses identified 63 novel loci suggestively associated with BP. As expected, most of these variants (81%) had minor allele frequencies (MAFs)<1%. Although none achieved genome-wide significance (P<5х10
-8
) in joint analyses of discovery and replication stages, two rare variants had consistent effect directions and achieved nominal significance in replication analyses, including one for DBP at
CHL1
(rs932205533; MAF=1.2х10
-4
; joint β=18.0; joint P=7.4х10
-8
) and one for SBP at
MACROD2
(rs752530366; MAF=8.6х10
-4
; joint β=-5.1; joint P=3.8х10
-6
). A total of 44 novel variants from previously reported loci (r
2
<0.1 with previously reported variants) were also identified in the discovery stage analyses, including 31 rare variants with large effect sizes (70%). Nine common variants from these loci achieved genome-wide significance in joint analyses. Variants for SBP included ones at
NPPB
(rs12406089; MAF=0.34; joint β=-0.58; joint P=2.7х10
-79
),
AC137675.1
(rs2643826; MAF=0.56; joint β=0.56; joint P=1.5х10
-45
),
NEIL2
(rs804264; MAF=0.35; joint β=0.28; joint P=4.7х10
-20
),
CACNB2
(rs11014204; MAF=0.21; joint β=-0.53; joint P=6.8х10
-57
),
OVOL1
(rs557675; MAF=0.43; joint β=-0.25; joint P=1.9х10
-17
),
RP11-654D12.2
(rs8014582; MAF=0.05; joint β=-0.52; joint P=6.7х10
-13
), and
ATXN2
(rs35350651; MAF=0.67; joint β=-0.39; joint P=3.4х10
-38
). Novel variants for DBP at
INSR
(rs36150639; MAF=0.45; joint β=-0.29; joint P=2.5х10
-27
) and HTN at
TBX3
(rs2891546; MAF=0.17; joint OR=0.95; joint P=3.1х10
-14
) were also identified.

Conclusion:
WGS studies in large multi-ancestry samples can identify novel signals at previously reported GWAS loci, helping to localize causal genes and variants for BP.