Genome wide association studies will unlock the
genetic basis of human hypertension
Anna F Dominiczak
GWAS – a watershed in the history of
genetics in medicine
• associations with common SNPs identified in GWAS have
proven robust and reproducible
• as per design – most of these SNPs are associated with a
relative risk of 1.5 per copy or less – thus even in aggregate
account for a small fraction of the overall inherited risk
• the mechanisms whereby DNA variation in most of these
regions influences disease is not obvious  good, more
work is needed!
GWAS & hypertension
• WTCCC published in 2007 = first GWAS for
hypertension – no SNPs crossing experimental
threshold of significance (px10-7)
• 8 further GWAS for BP or hypertension have
been published since ( European, Japanese,
Korean, African Americans, and Amish
ancestry)
Examples of success
• cluster of SNPs on chr 2q24.3 with serine theronine kinase 39 (STK39)
initial P=8.9x10-6 (Amish cohort), meta-analysis P=1.6x10-7 (n>7000
individuals) & relevant protein interacts with cation transporters in the
kidney
Wang et al, PNAS 2009
• KORA (Europeans), SNP upstream T-cadherin (CDH13) gene on chr
16q23.3 associated with DBP, initial P=5.55x10-5, replication P=5.3 x10-8
Org et al, Hum Mol Genet 2009
• Korean cohort, two SNPs associated with SBP & DBP, initial P=9.1x10-7,
replication P= 1.3x10-7, intragenic SNP near the ATPase calcium ion
transporting membrane 1 gene (ATP2B1) - protein involved in calcium
homeostasis
Cho et al, Nat Genet 2009
Meta-analysis of GWAS for BP & Hypertension
• 2009, two large-scale meta-analyses of GWAS for BP and
hypertension published (Global BPGen & CHARGE)
• more stringent significance threshold (p < 5x10-8)
• genome imputation approaches to combine data across
cohorts that used different SNP genotyping chips
• SBP & DBP in both consortia plus genome scan for
hypertensive genes in CHARGE
• both consortia identified genome-wide significant
associations at 8 loci with 3 discovered by both consortia
GWAS hits for blood pressure and hypertension
(at p< 5x10-8)
MTHFR
NPPA
CLCN6
NPPB
AGTRAP
CASZ1
ULK4
PLEKHA7
CACNB2
FGF5
PRDM8
c4orf22
c10orf107
TMEM26
RTKN2
RHOBTB1
ARID5B
MDS1
1
3
4
10
CYP17A1
AS3MT
CNNM2
NT5C2
ATP2B1
11
12
SH2B3
ATXN2
TBX3
TBX5
15
CSK
ULK3
CYP1A1
CYP1A2
CSK
LMAN1L
ARID3B
Newton Cheh et al, Nat Gen 2009 (chr 1,3,10,12,15,17)
Levy et al, Nat Gen 2009 (chr 3,10,11,12,15)
PLCD3
ACBD4
HEX1M1
HEX1M2
ZNF652
PHB
16
CDH13
17
New Candidate Loci for Hypertension
• Meta-analyses of GWAS results have revealed 13 new
candidates loci for BP and hypertension
• Two of 13 genomic regions contain genes that have
been previously implicated in hypertension
susceptibility:
• Chr 1p32, atrial natriuretic peptide A and B-type
natriuretic peptide genes NPPA & B
• Chr10q24, CYP17A1 gene- (mutations  17-ahydoxylase CAH)
Critics of GWAS might tell you that:
• small effects of multiple genes
• the modest fraction of heritability
explained
• and lack of overlap with our biologic understanding
• all suggest a weakness of genomics

I and many colleagues disagree
The origins of dislike/hate
• genetic mapping turns hypothesis – driven research
on its head as it is based on the theory that
systematic genome-wide study of DNA variation
will lead us to disease genes
• very large sample sizes are required to pinpoint
novel disease causing genes and very stringent
level of statistical significance is required i.e. only
collaborative big ventures win
The Genetic Architecture of BP
• each SNP explains a very small proportion of the total
variation in SBP & DBP, 0.05-0.10% or 1mmHg/allele
systolic and 0.5mmHg/allele diastolic BP
• but the aggregate effects of several variants do produce
meaningful population changes in risk
• 2mmHg SBP  6% reduction of stroke & 5% reduction of
CAD
• there are many more common variants associated with BP
that remain to be discovered
Future
• ongoing even larger meta-analyses of GWAS =
International Consortium for BP-Genome-Wide
Association Study (ICBP-GWAS)
• studies targeting individuals with extreme phenotypes
• careful analysis of CNVs
• data from the 1000 Genomes Project open the possibility
of reliable imputation of rare variant genotypes
• resequencing (next-generation) of cases and controls for
fine mapping & causal variants
Feasibility of identifying genetic variants by risk allele
frequency and strength of genetic effect
Manolio et al, Nature 2009
GWAS & opportunities for physician scientists
• rather than seeking a new twist on a long-studied
pathway or asking whether discoveries in model
organisms are relevant to humans, researchers can
explore hundreds of genes proven by GWAS to be
relevant to human disease
• the challenge is to develop research methods to take
us from genetic localisation to medically useful
application
“As for the future, your task is
not to foresee, but to enable it”
Antoine de Saint – Exupéry
The Wisdom of the Sands