supplementary materials variants near terc are · pdf file1 supplementary materials . variants...
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SUPPLEMENTARY MATERIALS
Variants near TERC are associated with mean telomere length.
Veryan Codd1*, Massimo Mangino2*, Pim van der Harst1,3*, Peter S Braund1, Michael Kaiser1,
Alan J Beveridge1, Suzanne Rafelt1, Jasbir Moore1, Chris Nelson1, Nicole Soranzo2,4, Guangju
Zhai2, Ana M Valdes2, Hannah Blackburn2, Irene Mateo Leach3, Rudolf A de Boer3, Wellcome
Trust Case Control Consortium5, Alison H Goodall1, Willem Ouwehand6, Dirk J. van Veldhuisen3,
Wiek H. van Gilst3, Gerjan Navis7, Paul R Burton8, Martin D Tobin8, Alistair S Hall9, John R
Thompson8, Tim Spector2#, Nilesh J Samani1#
Nature Genetics: doi:10.1038/ng.532
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Supplementary Figure 1: Distribution of telomere lengths, age-relationship of telomere length, quantile-quantile plots of observed versus expected associations and power to detect associations.
BHF-FHS UKBS
0.5
11
.52
Den
sity
.5 1 1.5 2 2.5T/S
0.5
11
.5
Den
sity
1 1.5 2 2.5 3trf
20 40 60 80 1000.0
0.5
1.0
1.5
2.0
2.5
Age (years)
T/S
0 20 40 60 80 1000
1
2
3
4
Age (years)
T/S
A
B
C
D
Nature Genetics: doi:10.1038/ng.532
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Legend to Supplementary Figure 1: Panel A shows the distribution of mean leucocyte mean
telomere length in BHF-FHS and UKBS cohorts. Telomere length was normally distributed in
both cohorts. Panel B shows telomere length as a function of age at recruitment in the two
cohorts. Both cohorts showed the expected decline in telomere length in individuals of
increasing age. Regression lines are shown in black. Telomere length declined by 0.0063 T/S
per year (r2 = 0.052, P
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Supplementary Table 1: Characteristics of the cohorts studied
Cohort No. of subjects Age (years)
Mean +/- SD
(range)
Gender
M/F (%)
Leucocyte telomere length*
Mean +/- SD (range)
BHF-FHS 1487 60.87.9 (36-82) 80.1/19.9 1.3520.216 (0.69-2.13)
UKBS 1430 43.412.4 (17-69) 48.4/51.6 1.7960.50 (0.80-3.01)
GRAPHIC# 2020 39.314.5 (18-60) 50.5/49.5 1.6040.258 (0.50-3.01)
TWINSUK 3256 48.6113.08 (18-82) 7.6/92.4 6.980.685 (5.09-9.37)
PREVEND 4216 49.3812.80(28-75) 52/48 0.8170.393 (0.14-2.14)
More details of the cohorts are given in Supplementary Methods. BHF-FHS, British Heart
Foundation Family Heart Study; UKBS, National Blood Service donors; *Mean telomere lengths
in BHF-FHS, UKBS, GRAPHIC, and PREVEND are based on PCR-based quantification and
expressed as T/S ratio while that in TwinsUK is based on Southern blotting and expressed in
kilobases. PREVEND used a different calibrator sample in the PCR assay to BHF-FHS, UKBS and
GRAPHIC; hence the different mean T/S ratio in this study (see Supplementary Method for
more details). #The GRAPHIC data are summarised for the two generations combined. The
mean age and mean leucocyte lengths for the parental and offspring generations were:
52.84.4 , 1.510.23 and 25.55.3, 1.700.26, respectively.
Nature Genetics: doi:10.1038/ng.532
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Supplementary Table 2: List of top SNPs (P
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2B
UKBS BHF-FHS
CHR SNP BP A1 MAF N BETA (SE)
P BETA P
15 rs8032144 96175496 A 0.49 1421 -0.0558 (0.012)
2.28x10-6
-0.005 0.56
1 rs12130746 212361952 G 0.07 1415 -0.110 (0.023)
2.40x10-6
0.013 0.39
12 rs7960152 99078240 A 0.22 1322 0.069 (0.015)
2.58x10-6
-0.007 0.47
9 rs10817041 110416280 C 0.34 1420 -0.054 (0.012)
4.37x10-6
-0.004 0.62
16 rs2052873 70062800 T 0.15 1421 0.073 (0.016)
4.43x10-6
-0.012 0.27
9 rs10817042 110436016 T 0.34 1419 -0.052 (0.012)
1.22x10-5
-0.003 0.73
13 rs17073170 28764736 A 0.04 1419 0.127 (0.029)
1.26x10-5
0.013 0.53
16 rs16973260 70092352 T 0.15 1415 0.070 (0.016)
1.73x10-5
-0.014 0.18
16 rs16972808 70036216 C 0.15 1422 0.069 (0.016)
1.78x10-5
-0.012 0.24
12 rs4759709 129526352 C 0.41 1418 -0.051 (0.012)
2.06x10-5
0.003 0.74
18 rs1876978 64418208 A 0.43 1412 -0.048 (0.011)
3.37x10-5
-0.002 0.76
7 rs2160059 10802988 G 0.09 1422 0.083 (0.020)
3.54x10-5
0.019 0.17
1 rs1325939 119296008 T 0.25 1419 -0.055 (0.013)
3.64x10-5
0.012 0.17
7 rs17163856 10791039 C 0.09 1420 0.083 (0.020)
3.66x10-5
0.018 0.20
16 rs12922830 70004768 T 0.17 1415 0.063 (0.015)
3.81x10-5
-0.009 0.38
7 rs6954256 10886998 T 0.09 1418 0.080 (0.020)
4.48x10-5
0.020 0.13
5 rs13354399 153169632 A 0.27 1421 0.052 (0.013)
4.66x10-5
-0.005 0.60
10 rs11011867 20534772 G 0.36 1420 0.049 (0.012)
4.96x10-5
0.007 0.45
Nature Genetics: doi:10.1038/ng.532
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2C
BHF-FHS+UKBS BHF-FHS UKBS
CHR
SNP
BP
A1
MAF
N
BETA
(SE)
P
BETA
P
BETA
P
11
rs610160
105202104
C
0.13
2901
0.046
(0.010)
7.05x10-6
0.030
8.89x10-3
0.064
2.03x10-4
9
rs10511887
31827334
G
0.24
2851
-0.044
(0.010)
8.86x10-6
-0.037
7.41x10-4
-0.052
2.10x10-3
3
rs16847897
171050816
C
0.27
2906
-0.034
(0.008)
1.03x10-5
-0.033
1.25x10-4
-0.035
6.64x10-3
13
rs1231044
27244594
C
0.21
2906
0.036
(0.008)
1.42x10-5
0.032
7.83x10-4
0.041
3.04x10-3
11
rs41375749
105207526
A
0.12
2900
0.046
(0.011)
1.54x10-5
0.031
8.74x10-3
0.063
4.62x10-4
2
rs2592941
173642848
G
0.49
2897
-0.029
(0.007)
1.88x10-5
-0.028
2.50x10-4
-0.031
9.15x10-3
7
rs2694166
101565352
A
0.21
2907
-0.035
(0.0084)
2.44x10-5
-0.030
1.52x10-3
-0.042
2.75x10-3
9
rs11791705
18768724
A
0.19
2869
-0.036
(0.009)
3.20 x10-5
-0.035
4.44 x10-4
-0.040
9.50x10-3
11
rs10488675
5254606
G
0.27
2878
-0.032
(0.008)
3.38 x10-5
-0.025
4.31x10-3
-0.041
1.71x10-3
5
rs17281015
19486232
G
0.23
2909
0.034
(0.008)
3.65 x10-5
0.033
2.95 x10-4
0.035
0.013
1
rs17597773
217443152
G
0.24
2906
-0.033
(0.008)
3.97 x10-5
-0.023
0.013
-0.042
1.47 x10-3
8
rs1398482
5650310
G
0.24
2858
-0.034
(0.008)
4.23 x10-5
-0.027
3.46 x10-3
-0.041
3.23 x10-3
15
rs1435682
34197464
G
0.20
2900
0.035
(0.008)
4.46 x10-5
0.022
0.029
0.049
6.88 x10-4
15
rs16976218
53325840
A
0.09
2903
-0.049
(0.012)
4.61 x10-5
-0.042
2.37 x10-3
-0.054
5.57 x10-3
11
rs1032779
100019120
A
0.26
2904
-0.032
(0.008)
4.88 x10-5
-0.024
7.21 x10-3
-0.038
2.48 x10-3
In each panel, markers (SNP) are given along with chromosomal (CHR) and base pair (bp)
positions (estimated from HapMap build35). Minor allele (A1) and frequency (MAF) and the
number of individuals (N) included in the analysis for each SNP are also stated. The effect size
(BETA) along with SE and the P-value of the association are shown. A negative beta indicates a
shorter mean telomere in those carrying the minor allele. In Tables A and B, to allow
comparison of the findings for the listed SNPs in the BHF-FHS and UKBS cohorts, the effect size
and corresponding P-values are given for the same marker in the other cohort (except for
markers which did not meet quality threshold criteria). In Table C (combined BHF-FHS and UKBS
analysis) only SNPs that had a combined P of < 1x10-5 and also showed concordance in data in
the individual analyses (nominally significant in both cohorts and showing the same direction of
effect) are shown. Data from the individual cohorts are also shown for these markers.
Nature Genetics: doi:10.1038/ng.532
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Supplementary Tables 3: Findings for previous loci and markers associated with telomere
length and additional covariate analysis in the TwinsUK cohort
3A: Analysis of previously reported genomic loci and markers for telomere length in the UKBS
and BHF-FHS GWAS data.
UKBS BHF-FHS
CHR NO. OF
SNPS IN
LOCUS
NO. OF
SNPS
P
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3B: Lack of effect of body mass index and smoking status on the association of the chromosome
3q26.2 SNPs with telomere length in the TwinsUK cohort.
Association results adj