NOVELTY AND SIGNIFICANCE
What is New: The root origin of hypertension and hence blood pressure variability in the population remains unclear. This study adds data to explain the genetic basis of blood pressure variability and identifies genes likely active in blood pressure regulating pathways.
What Is Relevant: The results are of relevance for scientists, clinicians, and pharmacologists interested in hypertension. The BP loci and the BP genes identified constitute new leads for the understanding of BP pathogenesis and possibly therapeutic innovation.
Summary: Using 1000 Genomes Project-based imputation in 150,134 European ancestry and independent replication in a further 228,245 individuals we contribute 8 replicated blood pressure loci to the collection of loci currently known. Using these and previous data, 48 BP genes are identified for priority follow-up.
FIGURE LEGENDS
Figure 1: Overlap of eQTL evidence from four whole-blood and one kidney resource
The figure indicates overlap of evidence for eQTLs from four whole-blood studies (SABRe, NESDA-NTR, BIOS, and GTEx) and from one kidney resource (TransplantLines). Every colored line indicates that this gene was analysis-wide significant in a given resource (see Online Methods). Only genes identified by at least two resources are shown. The genes are sorted by genomic position on the y-axis.
FIGURES
Figure 1
Table 1. Novel genome-wide significant signals of association
Results from stage 1 and stage 2, and the meta-analysis of stage 1 and stage 2, for all novel genome-wide significant signals of association. P values of association for all 3 traits from a meta-analysis of stages 1 and 2 are also presented. Genome-wide significant P values (P<5x10-8) are in bold. Abbreviations: CAF: coded allele frequency se: standard error, Neff: effective sample size. #Novel signal at previously reported locus. 1For intragenic variants the nearest genes are listed, all other variants are intronic unless indicated otherwise; ns= non-synonymous, s=synonymous, UTR= Untranslated Region. Results from proxy SNPs are indicated by (proxy); rs848309 was a proxy SNP for rs1048238 and rs10926988 was a proxy SNP for chr1:243458005:I.
|
|
Results for most significant trait
|
Stage 1 + stage 2 meta-analysis P values for all traits
|
|
|
Stage 1
|
Stage 2
|
Stage 1+ stage 2
|
Variant ID (noncoded/coded allele)
chr:position, Nearest gene(s)(type1)
|
CAF
|
Beta (se)
|
P value
|
Neff
|
Beta
(se)
|
P value
|
Neff
|
Beta (se)
|
P value
|
Neff
|
SBP
|
DBP
|
PP
|
SBP
|
rs1048238 (C/T)
1:16341649, HSPB7 (3’UTR)
|
0.571
|
0.366
(0.074)
|
8.09E-07
|
140299
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
rs848309(proxy) (T/C)
1:16308447
|
0.567
|
0.347
(0.072)
|
1.70E-06
|
146755
|
0.347
(0.071)
|
9.10E-07
|
140462
|
0.347
(0.051)
|
7.07E-12
|
287217
|
7.07E-12
|
1.07E-10
|
5.48E-06
|
#rs185819 (T/C)
6:32,050,067, TNXB (ns)
|
0.513
|
0.534
(0.073)
|
1.93E-13
|
142397
|
0.277
(0.053)
|
1.49E-07
|
221748
|
0.365
(0.043)
|
1.04E-17
|
364144
|
1.04E-17
|
2.24E-11
|
8.50E-15
|
rs6557876 (C/T)
8:25,900,675, EBF2
|
0.252
|
-0.411
(0.084)
|
8.50E-07
|
143653
|
-0.350
(0.060)
|
5.66E-09
|
225803
|
-0.371
(0.049)
|
2.85E-14
|
369457
|
2.85E-14
|
2.50E-10
|
1.51E-08
|
rs35783704 (G/A)
8:105,966,258, LRP12/ZFPM2
|
0.109
|
-0.609
(0.121)
|
4.96E-07
|
133924
|
-0.310
(0.089)
|
4.78E-04
|
215528
|
-0.414
(0.072)
|
7.08E-09
|
349452
|
7.08E-09
|
1.60E-06
|
2.92E-07
|
rs73099903 (C/T)
12:53,440,779, LOC283335
|
0.074
|
0.768
(0.143)
|
8.05E-08
|
136064
|
0.396
(0.098)
|
5.32E-05
|
207253
|
0.515
(0.081)
|
1.95E-10
|
343318
|
1.95E-10
|
4.53E-06
|
5.46E-08
|
rs8904 (G/A)
14:35,871,217, NFKBIA (3’ UTR)
|
0.375
|
0.377
(0.076)
|
6.76E-07
|
140424
|
0.278
(0.054)
|
2.31E-07
|
224771
|
0.311
(0.044)
|
1.31E-12
|
365195
|
1.31E-12
|
1.13E-04
|
3.44E-12
|
rs57927100 (C/G)
17:75,317,300, SEPT9
|
0.258
|
-0.489
(0.086)
|
1.10E-08
|
136624
|
-0.220
(0.061)
|
3.12E-04
|
210563
|
-0.310
(0.050)
|
4.04E-10
|
347188
|
4.04E-10
|
1.16E-10
|
1.81E-05
|
DBP
|
|
|
|
|
|
|
|
|
|
|
|
|
|
rs9710247 (A/G)
19:40,760,449, AKT2
|
0.447
|
0.252
(0.051)
|
8.11E-07
|
109695
|
0.129
(0.032)
|
5.76E-05
|
198332
|
0.164
(0.027)
|
1.61E-09
|
308028
|
3.82E-02
|
1.61E-09
|
5.03E-01
|
Table 2: BP associated SNPs associated with expression of the same gene across 4 or 3 independent whole-blood eQTL resources and the kidney resource. Signals of association of SNP genotype and gene expression in other non-blood tissues in GTEx and in kidney are also indicated. Blood dataset order: (i) SABRe, (ii) NESDA-NTR, (iii) BIOS, (iv) GTEx (whole-blood). Top eQTL: Top GWAS SNP is top eQTL SNP (or in high LD, r2>0.9, with top eQTL SNP) in at least one data set. eQTL signal previously reported: Genes for which eQTL signals have been previously reported for that sentinel SNP15-17. For full list, see Supplementary Table 12.
Sentinel SNP
|
Chr
|
Position
|
Gene
|
Blood data sets
|
Top eQTL
|
Signal in other tissue(s) in GTEx
|
Signal in kidney
|
eQTL signal previously reported
|
Signal in 4 whole-blood eQTL resources
|
rs17367504
|
1
|
11862778
|
CLCN6
|
YYYY
|
|
Y
|
|
Y
|
rs2169137
|
1
|
204497913
|
MDM4
|
YYYY
|
Y
|
Y
|
|
Y
|
rs10926988
|
1
|
243483279
|
SDCCAG8
|
YYYY
|
|
Y
|
|
|
rs319690
|
3
|
47927484
|
MAP4
|
YYYY
|
Y
|
Y
|
|
Y
|
rs12521868
|
5
|
131784393
|
SLC22A5
|
YYYY
|
|
Y
|
|
|
rs900145
|
11
|
13293905
|
ARNTL
|
YYYY
|
|
Y
|
|
Y
|
rs1060105
|
12
|
123806219
|
CDK2AP1
|
YYYY
|
Y
|
Y
|
Y
|
|
rs1378942
|
15
|
75077367
|
SCAMP2
|
YYYY
|
|
|
|
|
rs1126464
|
16
|
89704365
|
CHMP1A
|
YYYY
|
|
Y
|
|
Y
|
rs1126464
|
16
|
89704365
|
FANCA
|
YYYY
|
|
|
|
Y
|
rs12946454
|
17
|
43208121
|
DCAKD
|
YYYY
|
|
Y
|
Y
|
Y
|
Signal in 3 (out of 4) whole-blood eQTL resources
|
rs17367504
|
1
|
11862778
|
MTHFR
|
YYYN
|
|
Y
|
|
Y
|
rs871524
|
1
|
38411445
|
FHL3
|
NYYY
|
|
Y
|
|
|
rs871524
|
1
|
38411445
|
SF3A3
|
NYYY
|
|
Y
|
|
|
rs4660293
|
1
|
40028180
|
PABPC4
|
YYYN
|
Y
|
Y
|
|
Y
|
rs6749447
|
2
|
169041386
|
STK39
|
YYYN
|
Y
|
|
|
|
rs347591
|
3
|
11290122
|
ATG7
|
YYYN
|
|
Y
|
|
|
rs319690
|
3
|
47927484
|
ZNF589
|
YYNY
|
|
Y
|
|
|
rs12521868
|
5
|
131784393
|
SLC22A4
|
YYYN
|
|
Y
|
|
|
rs1563788
|
6
|
43308363
|
CRIP3
|
YYYN
|
Y
|
|
|
Y
|
rs10943605
|
6
|
79655477
|
PHIP
|
YYYN
|
Y
|
Y
|
|
Y
|
rs4728142
|
7
|
128573967
|
IRF5
|
NYYY
|
|
Y
|
Y
|
Y
|
rs4728142
|
7
|
128573967
|
TNPO3
|
YYYN
|
|
|
Y
|
|
rs2898290
|
8
|
11433909
|
BLK
|
YYYN
|
|
Y
|
|
|
rs2898290
|
8
|
11433909
|
FAM167A
|
NYYY
|
|
Y
|
|
|
rs2898290
|
8
|
11433909
|
FDFT1
|
YYYN
|
|
Y
|
|
|
rs2071518
|
8
|
120435812
|
NOV
|
YYYN
|
|
Y
|
|
|
rs76452347
|
9
|
35906471
|
TPM2
|
YYYN
|
|
|
|
|
rs10760117
|
9
|
123586737
|
MEGF9
|
YYYN
|
|
Y
|
|
Y
|
rs4494250
|
10
|
96563757
|
HELLS
|
YYYN
|
|
|
|
Y
|
rs11191548
|
10
|
104846178
|
NT5C2
|
YYYN
|
Y
|
|
|
|
rs661348
|
11
|
1905292
|
TNNT3
|
NYYY
|
|
Y
|
|
|
rs2649044
|
11
|
9763969
|
SBF2
|
YYYN
|
|
|
|
|
rs2649044
|
11
|
9763969
|
SWAP70
|
YYYN
|
Y
|
Y
|
|
?
|
rs7129220
|
11
|
10350538
|
ADM
|
YYYN
|
|
|
|
Y
|
rs7103648
|
11
|
47461783
|
MYBPC3
|
YYYN
|
|
|
|
|
rs3741378
|
11
|
65408937
|
CTSW
|
YYYN
|
|
|
|
|
rs7302981
|
12
|
50537815
|
LIMA1
|
YYYN
|
|
|
|
Y
|
rs7302981
|
12
|
50537815
|
ATF1
|
YYNY
|
|
Y
|
|
|
rs1036477
|
15
|
48914926
|
FBN1
|
YNYY
|
|
|
|
|
rs1378942
|
15
|
75077367
|
CSK
|
YYYN
|
Y
|
Y
|
|
Y
|
rs1378942
|
15
|
75077367
|
MPI
|
NYYY
|
|
Y
|
|
|
rs1378942
|
15
|
75077367
|
ULK3
|
YNYY
|
|
Y
|
|
Y
|
rs12946454
|
17
|
43208121
|
NMT1
|
YYYN
|
|
|
|
Y
|
rs2304130
|
19
|
19789528
|
GATAD2A
|
YYYN
|
|
|
|
|
rs867186
|
20
|
33764554
|
EIF6
|
NYYY
|
|
Y
|
|
|
rs6095241
|
20
|
47308798
|
PREX1
|
YYYN
|
|
|
|
|
rs9306160
|
21
|
45107562
|
RRP1B
|
YNYY
|
Y
|
Y
|
|
|
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