Supplementary Figure 1: Plot of estimated relative risks (RRs) from:
(i) the polygenic segregation model (Table 3);
(ii) logistic regression model comparing AOCS controls and all familial cases (Table 2)
and;
(iii) population-based estimates (Supplementary Table 1).
The 95% CI for the population-based estimates is also displayed.
The dashed line represents a relative risk of 1 (i.e. no association).
SNPs are ordered by magnitude of the published population-based ORs.
Estimates from the polygenic segregation model generally better agree with the
population-based estimates than do those from the logistic regression analyses.
19p13 SNPs rs2363956 and rs8170 are not displayed as they are associated with ERnegative breast cancer.
HR = hazard ratio; OR = odds ratio; CI = confidence interval.
Supplementary Figure 2: Density plots of the observed risk score (ORS) based on 22
SNPs.
The three curves are the observed risk score distributions for:
(i) population-based controls from the AOCS study (n = 715);
(ii) unaffected females with family history of breast cancer from the kConFab study (n =
64) and;
(iii) affected women with family history of breast cancer from the kConFab study (n =
432).
Supplementary Table 1: Population-based breast cancer associations for the SNPs analysed (ordered by strength
of association)
Gene/
Region
SNP
Alleles*
Affected/
Unaffected
FGFR2
rs2981582
10
RAF
OR (95% CI)**
123352317
C/T
22,848/22,578
0.38
1.26 (1.23-1.30)
2.00x10-76
12p11 †
rs1975930
E
12
28046347
A/G
59,006/58,822
0.12
0.85 (0.83-0.88)
3.30x10-27
5p12
rs10941679
G
5
44706498
A/G
40,972/46,334
0.26
1.12 (1.10-1.15)
6.00 x10-24
M
-19
S
Chromosome
Position
p
R
TOX3
rs3803662
16
52586341
C/T
45,54/17,577
0.269
1.28 (1.21-1.35)
5.90 x10
6q25.1
rs2046210
6
151948366
G/A
49,634/46,679
0.33
1.09 (1.07-1.11)
6.76 x10-18
H
11q13
rs614367
11
69328764
C/T
12,114/11,967
0.15
1.15 (1.10-1.20)
3.20 x10-15
T
ZNF365 ‡
rs10509168
10
64257828
G/A
12,261/12,000
0.15
0.86 (0.82-0.91)
5.10 x10-15
T
12q24
rs1292011
12
115836522
A/G
59,006/58,822
0.41
0.92 (0.91-0.94)
6.20 x10-14
G
2q35
rs13387042
2
217905832
G/A
1,599/11,546
0.497
1.20 (1.14-1.26)
1.30 x10-13
S
-12
E
8q24
rs13281615
8
128355618
A/G
22,848/22,578
0.4
1.08 (1.05-1.11)
5.00 x10
9q31.2
rs865686
9
110888478
T/G
11,781/12,387
0.39
0.89 (0.85-0.92)
1.75 x10-10
F
EMBP1
rs11249433
1
121280613
T/C
9,335/10,263
0.39
1.16 (1.09-1.24)
6.74 x10-10
T
21q21
rs2823093
21
16520832
G/A
59,006/58,822
0.27
0.94 (0.92-0.96)
1.70 x10-9
G
LSP1
rs3817198
11
1909006
T/C
22,848/22,578
0.3
1.07 (1.04-1.11)
3.00 x10-9
E
-9
T
MAP3K1
rs889312
5
56031884
A/C
3,659/4,897
0.28
1.22 (1.14-1.30)
4.60 x10
CDKN2B
rs1011970
9
22062134
G/T
12,253/12,000
0.17
1.09 (1.04-1.14)
2.50 x10-8
T
ALS2CR12 §
rs17468277
2
202154200
C/T
16,423/17,109
0.13
0.88 (0.84-0.92)
1.10 x10-7
C
RAD51B
rs999737
14
69034682
T/C
9,395/10,298
0.76
1.06 (1.01-1.14)
1.74 x10-7
T
ANKRD16/FBXO18
rs2380205
10
5886734
C/T
12,235/11,961
0.43
0.94 (0.91-0.98)
4.60 x10-7
T
SLC4A7
rs4973768
3
27416013
C/T
3,659/4,897
0.47
1.16 (1.10-1.24)
5.80 x10-7
T
STXBP4
rs6504950
17
53056471
G/A
30,470/33,302
0.27
0.95 (0.92-0.97)
0.0001
A
19p13 ¶
rs2363956
19
17394124
A/C
833/6,603
0.507
0.83 (0.75-0.92)
0.0003
A
19p13 ¶
rs8170
19
17389704
G/A
819/6,516
0.189
1.21 (1.07-1.37)
0.0029
A
C6orf97
rs12662670
6
151918856
T/G
7,899/11,234
0.071
1.12 (1.03-1.21)
0.0064
S
RAF = risk allele frequency; OR = odds ratio; CI = confidence interval
* Non-risk/risk allele
** All ORs are per-allele unless otherwise stated
† Proxy SNP rs10771399 (r2 = 0.95) was reported; ‡ Proxy SNP ZNF365 rs10995190 was reported;
§ rs17468277 is a proxy for SNP for SNP CASP8 D302H rs1045485 (r2 = 1.00); ¶ ER-negative breast cancer
association reported
Supplementary Table 2: Meta-analysis pooling parent-of-origin associations for SNP rs3817198 in the LSP1 gene
Maternal
effect
Paternal
effect
Study
Kong et al
kConFab/AOCS
Meta-analysis
Unaffected/
affected
34,909/1,803
3,588/1,463
38,497/3,266
β
-0.0943
-0.0580
-0.0766
σ
0.0582
0.0595
0.0416
Weight (%)
51.09
48.91
RR (95% CI)
0.91 (0.81-1.02)
0.94 (0.84-1.06)
0.93 (0.85-1.01)
p
0.11
0.33
0.07
Kong et al
kConFab/AOCS
Meta-analysis
34,909/1,803
3,588/1,463
38,497/3,266
0.1570
0.1119
0.1384
0.0538
0.0641
0.0412
58.72
41.28
1.17 (1.05-1.30)
1.12 (0.99-1.27)
1.15 (1.06-1.24)
0.0038
0.0810*
0.0008
RR = relative risk; CI = confidence interval; β = estimated log-RR; σ = estimated standard error for the log-RR
RR is an odds ratio (OR) in the case of Kong et al and is a hazard ratio (HR) for the kConFab/AOCS analysis
Weights were calculated by inverse variance weighting
The reported effect allele for SNP rs3817198 was the C allele (other allele = T).
* p-value when testing HR > 1 was 0.040