Supplementary Table S1. Effect Estimates for Inherited Genetic Effects of Previous Breast

Supplementary Figure S1. Quantile-quantile plot for p-values from t-tests comparing our young-onset breast cancer effect estimates to those reported in Mavaddat et al. [1] for overall breast cancer

Supplementary Table S1. Effect estimates for inherited genetic effects of previous breast cancer genome-wide association study risk variants on the risk of invasive young-onset breast cancer (Two Sister Study, 2008-2012)

Rank / SNP / RR (95% CI) / p-value
1
/ rs3803662 / 1.37 (1.17, 1.60) / 5.7 x 10-5
2 / rs12662670 / 1.66 (1.24, 2.23) / 5.1 x 10-4
3 / rs2981579 / 1.28 (1.10, 1.49) / 0.001
4 / rs999737 / 1.26 (1.06, 1.49) / 0.008
5 / rs4849887 / 1.35 (1.08, 1.69) / 0.008
6 / rs13281615 / 1.20 (1.03, 1.39) / 0.02
7 / rs6001930 / 1.31 (1.04, 1.64) / 0.02
8 / rs554219 / 1.28 (1.03, 1.60) / 0.02
9 / rs6828523 / 1.29 (1.03, 1.63) / 0.03
10 / rs10759243 / 1.21 (1.01, 1.43) / 0.03
11 / rs12493607 / 1.18 (1.01, 1.38) / 0.04
12 / rs2046210 / 1.18 (1.01, 1.37) / 0.04
13 / rs941764 / 1.17 (1.00, 1.36) / 0.04
14 / rs1436904 / 1.16 (1.00, 1.34) / 0.05
15 / rs2943559 / 1.29 (1.00, 1.66) / 0.05
16 / rs7072776 / 0.87 (0.74, 1.01) / 0.07
17 / rs1011970 / 1.18 (0.98, 1.43) / 0.08
18 / rs720475 / 1.16 (0.98, 1.36) / 0.08
19 / rs10941679 / 1.17 (0.98, 1.39) / 0.08
20 / rs75915166 / 1.32 (0.96, 1.81) / 0.08
21 / rs11199914 / 1.15 (0.98, 1.34) / 0.09
22 / rs3903072 / 1.13 (0.98, 1.30) / 0.10
23 / rs2736108 / 1.18 (0.97, 1.43) / 0.10
24 / rs10472076 / 1.13 (0.97, 1.31) / 0.11
25 / rs7726159 / 1.18 (0.96, 1.46) / 0.12
26 / rs4973768 / 1.11 (0.97, 1.28) / 0.14
27 / rs616488 / 1.12 (0.96, 1.30) / 0.15
28 / rs78540526 / 1.24 (0.92, 1.66) / 0.15
29 / rs11242675 / 1.11 (0.96, 1.29) / 0.15
30 / rs11075995 / 0.89 (0.75, 1.05) / 0.16
31 / rs11780156 / 1.13 (0.94, 1.36) / 0.18
32 / rs12710696 / 1.10 (0.96, 1.28) / 0.18
33 / rs9693444 / 1.11 (0.95, 1.29) / 0.19
34 / rs17356907 / 1.11 (0.94, 1.31) / 0.21
35 / rs2363956 / 0.91 (0.79, 1.05) / 0.21
36 / rs17529111 / 1.12 (0.93, 1.35) / 0.22
37 / rs11249433 / 1.08 (0.93, 1.26) / 0.29
38 / rs6472903 / 1.10 (0.91, 1.33) / 0.32
39 / rs2236007 / 1.09 (0.92, 1.29) / 0.33
40 / rs4245739 / 1.08 (0.91, 1.27) / 0.38
41 / rs12422552 / 0.94 (0.80, 1.10) / 0.43
42 / rs704010 / 1.06 (0.92, 1.23) / 0.43
43 / rs1292011 / 1.05 (0.91, 1.22) / 0.47
44 / rs11814448 / 0.85 (0.54, 1.33) / 0.48
45 / rs2016394 / 1.05 (0.91, 1.21) / 0.48
46 / rs4808801 / 1.06 (0.90, 1.23) / 0.49
47 / rs204247 / 1.05 (0.91, 1.21) / 0.50
48 / rs16857609 / 0.95 (0.81, 1.12) / 0.53
49 / rs2588809 / 0.94 (0.78, 1.14) / 0.54
50 / rs132390 / 1.14 (0.71, 1.83) / 0.58
51 / rs13387042 / 1.04 (0.90, 1.20) / 0.58
52 / rs10995190 / 1.06 (0.86, 1.30) / 0.60
53 / rs1550623 / 1.05 (0.87, 1.28) / 0.60
54 / rs10771399 / 1.06 (0.85, 1.33) / 0.61
55 / rs1045485 / 1.06 (0.85, 1.31) / 0.61
56 / rs527616 / 1.05 (0.87, 1.26) / 0.63
57 / rs7904519 / 0.97 (0.83, 1.12) / 0.66
58 / rs6762644 / 0.97 (0.84, 1.12) / 0.66
59 / rs11820646 / 0.97 (0.83, 1.13) / 0.67
60 / rs6678914 / 0.97 (0.84, 1.12) / 0.68
61 / rs865686 / 1.03 (0.89, 1.20) / 0.69
62 / rs9790517 / 1.03 (0.88, 1.22) / 0.70
63 / rs889312 / 1.03 (0.88, 1.20) / 0.71
64 / rs6504950 / 1.03 (0.87, 1.22) / 0.73
65 / rs2823093 / 1.03 (0.88, 1.20) / 0.73
66 / rs13329835 / 0.97 (0.82, 1.16) / 0.76
67 / rs3817198 / 1.02 (0.88, 1.19) / 0.78
68 / rs11552449 / 0.98 (0.81, 1.18) / 0.80
69 / rs10069690 / 0.99 (0.84, 1.15) / 0.85
70 / rs8170 / 1.02 (0.85, 1.22) / 0.86
71 / rs1353747 / 0.98 (0.77, 1.25) / 0.88
72 / rs17817449 / 0.99 (0.86, 1.14) / 0.88
73 / rs2380205 / 1.01 (0.88, 1.16) / 0.90
74 / rs1432679 / 1.01 (0.87, 1.16) / 0.91
75 / rs3760982 / 1.00 (0.86, 1.15) / 0.97

Supplementary Table S2. Effect estimates for inherited genetic effects of previous breast cancer genome-wide association study risk variants on the risk of estrogen receptor positive (ER+) young-onset breast cancer (Two Sister Study, 2008-2012)

Rank / SNP / RR (95% CI) / p-value
1
/ rs3803662 / 1.43 (1.22, 1.69) / 1.1 x 10-5
2 / rs10759243 / 1.37 (1.14, 1.64) / 5.4 x 10-4
3 / rs2981579 / 1.29 (1.11, 1.51) / 7.6 x 10-4
4 / rs999737 / 1.31 (1.10, 1.56) / 0.002
5 / rs720475 / 1.29 (1.09, 1.51) / 0.002
6 / rs12662670 / 1.46 (1.09, 1.96) / 0.009
7 / rs7726159 / 1.33 (1.06, 1.67) / 0.01
8 / rs6828523 / 1.34 (1.06, 1.71) / 0.02
9 / rs10941679 / 1.22 (1.02, 1.45) / 0.03
10 / rs2736108 / 1.25 (1.02, 1.52) / 0.03
11 / rs2943559 / 1.34 (1.03, 1.76) / 0.03
12 / rs554219 / 1.26 (1.01, 1.57) / 0.03
13 / rs941764 / 1.18 (1.01, 1.38) / 0.04
14 / rs1292011 / 1.17 (1.01, 1.35) / 0.04
15 / rs865686 / 1.17 (1.00, 1.36) / 0.05
16 / rs10472076 / 1.16 (1.00, 1.35) / 0.05
17 / rs11199914 / 1.18 (1.00, 1.39) / 0.05
18 / rs527616 / 1.19 (0.99, 1.44) / 0.06
19 / rs4973768 / 1.15 (0.99, 1.33) / 0.07
20 / rs75915166 / 1.32 (0.97, 1.80) / 0.07
21 / rs4849887 / 1.23 (0.98, 1.54) / 0.07
22 / rs1436904 / 1.15 (0.99, 1.33) / 0.08
23 / rs616488 / 1.15 (0.98, 1.34) / 0.08
24 / rs7904519 / 0.89 (0.76, 1.03) / 0.13
25 / rs3817198 / 1.13 (0.97, 1.31) / 0.13
26 / rs11780156 / 1.15 (0.96, 1.39) / 0.13
27 / rs1011970 / 1.16 (0.95, 1.41) / 0.13
28 / rs1045485 / 1.19 (0.95, 1.48) / 0.14
29 / rs6001930 / 1.18 (0.94, 1.49) / 0.15
30 / rs7072776 / 0.89 (0.77, 1.05) / 0.16
31 / rs6762644 / 0.90 (0.77, 1.05) / 0.17
32 / rs2046210 / 1.11 (0.95, 1.30) / 0.17
33 / rs6678914 / 0.90 (0.78, 1.05) / 0.17
34 / rs13281615 / 1.11 (0.95, 1.29) / 0.18
35 / rs6472903 / 1.13 (0.93, 1.37) / 0.23
36 / rs12493607 / 1.10 (0.94, 1.28) / 0.25
37 / rs10771399 / 1.14 (0.91, 1.44) / 0.26
38 / rs3903072 / 1.09 (0.94, 1.25) / 0.26
39 / rs11552449 / 0.90 (0.75, 1.09) / 0.28
40 / rs11820646 / 0.92 (0.79, 1.07) / 0.29
41 / rs9693444 / 1.09 (0.93, 1.27) / 0.30
42 / rs889312 / 1.09 (0.93, 1.27) / 0.31
43 / rs11075995 / 0.92 (0.78, 1.09) / 0.34
44 / rs13387042 / 1.07 (0.92, 1.24) / 0.35
45 / rs2236007 / 1.08 (0.91, 1.29) / 0.36
46 / rs132390 / 1.25 (0.76, 2.06) / 0.38
47 / rs11814448 / 1.23 (0.77, 1.97) / 0.39
48 / rs2363956 / 0.94 (0.81, 1.09) / 0.39
49 / rs11249433 / 1.07 (0.92, 1.24) / 0.40
50 / rs17356907 / 1.07 (0.91, 1.27) / 0.43
51 / rs17817449 / 1.05 (0.91, 1.22) / 0.51
52 / rs1432679 / 0.95 (0.82, 1.11) / 0.53
53 / rs12710696 / 1.05 (0.90, 1.22) / 0.53
54 / rs11242675 / 1.05 (0.90, 1.22) / 0.53
55 / rs2823093 / 1.05 (0.89, 1.24) / 0.55
56 / rs2380205 / 1.04 (0.90, 1.21) / 0.56
57 / rs3760982 / 1.04 (0.90, 1.21) / 0.60
58 / rs17529111 / 1.05 (0.87, 1.27) / 0.60
59 / rs204247 / 1.04 (0.90, 1.20) / 0.61
60 / rs12422552 / 0.96 (0.82, 1.13) / 0.64
61 / rs6504950 / 1.03 (0.87, 1.22) / 0.70
62 / rs4245739 / 1.03 (0.87, 1.22) / 0.73
63 / rs9790517 / 1.03 (0.87, 1.22) / 0.73
64 / rs8170 / 0.97 (0.80, 1.17) / 0.76
65 / rs2016394 / 1.02 (0.88, 1.18) / 0.78
66 / rs1550623 / 1.03 (0.84, 1.25) / 0.79
67 / rs13329835 / 0.98 (0.82, 1.17) / 0.82
68 / rs10995190 / 1.02 (0.83, 1.25) / 0.85
69 / rs10069690 / 1.01 (0.86, 1.19) / 0.88
70 / rs2588809 / 1.01 (0.83, 1.23) / 0.88
71 / rs4808801 / 1.01 (0.86, 1.19) / 0.91
72 / rs78540526 / 1.01 (0.75, 1.37) / 0.93
73 / rs16857609 / 1.00 (0.85, 1.18) / 0.97
74 / rs704010 / 1.00 (0.86, 1.16) / 0.99
75 / rs1353747 / 1.00 (0.79, 1.27) / 1.00

Supplementary Table S3. Effect estimates for inherited genetic effects of previous breast cancer genome-wide association study risk variants on the risk of premenopausal young-onset breast cancer (Two Sister Study, 2008-2012)

Rank / SNP / RR (95% CI) / p-value
1
/ rs3803662 / 1.39 (1.19, 1.61) / 1.4 x 10-5
2 / rs12662670 / 1.58 (1.21, 2.08) / 6.6 x 10-4
3 / rs999737 / 1.28 (1.09, 1.50) / 0.003
4 / rs2981579 / 1.23 (1.07, 1.42) / 0.003
5 / rs10759243 / 1.25 (1.06, 1.47) / 0.009
6 / rs11199914 / 1.21 (1.04, 1.41) / 0.01
7 / rs554219 / 1.28 (1.04, 1.57) / 0.02
8 / rs6001930 / 1.29 (1.04, 1.61) / 0.02
9 / rs720475 / 1.20 (1.03, 1.39) / 0.02
10 / rs2046210 / 1.18 (1.02, 1.37) / 0.02
11 / rs4849887 / 1.27 (1.03, 1.56) / 0.03
12 / rs10941679 / 1.20 (1.02, 1.41) / 0.03
13 / rs616488 / 1.18 (1.02, 1.36) / 0.03
14 / rs7726159 / 1.24 (1.01, 1.51) / 0.04
15 / rs6828523 / 1.26 (1.01, 1.58) / 0.04
16 / rs12493607 / 1.16 (1.00, 1.35) / 0.05
17 / rs3903072 / 1.14 (1.00, 1.31) / 0.05
18 / rs75915166 / 1.34 (1.00, 1.80) / 0.05
19 / rs13281615 / 1.15 (1.00, 1.32) / 0.05
20 / rs4973768 / 1.14 (1.00, 1.31) / 0.05
21 / rs11780156 / 1.18 (0.99, 1.40) / 0.06
22 / rs9693444 / 1.14 (0.98, 1.32) / 0.08
23 / rs2236007 / 1.14 (0.98, 1.34) / 0.09
24 / rs7072776 / 0.88 (0.76, 1.02) / 0.10
25 / rs941764 / 1.12 (0.97, 1.30) / 0.11
26 / rs10472076 / 1.12 (0.97, 1.29) / 0.12
27 / rs17356907 / 1.13 (0.97, 1.32) / 0.12
28 / rs2736108 / 1.15 (0.96, 1.37) / 0.14
29 / rs2943559 / 1.20 (0.94, 1.52) / 0.14
30 / rs1045485 / 1.16 (0.95, 1.43) / 0.15
31 / rs1011970 / 1.14 (0.95, 1.36) / 0.16
32 / rs11242675 / 1.10 (0.96, 1.27) / 0.17
33 / rs78540526 / 1.20 (0.91, 1.58) / 0.19
34 / rs1292011 / 1.09 (0.95, 1.25) / 0.20
35 / rs12710696 / 1.09 (0.95, 1.25) / 0.22
36 / rs1436904 / 1.09 (0.95, 1.25) / 0.24
37 / rs2016394 / 1.08 (0.94, 1.24) / 0.26
38 / rs9790517 / 1.09 (0.93, 1.28) / 0.27
39 / rs889312 / 1.08 (0.94, 1.25) / 0.29
40 / rs7904519 / 0.93 (0.81, 1.07) / 0.30
41 / rs11075995 / 0.92 (0.79, 1.08) / 0.30
42 / rs704010 / 1.07 (0.94, 1.23) / 0.31
43 / rs4245739 / 1.08 (0.93, 1.26) / 0.31
44 / rs17817449 / 1.07 (0.94, 1.23) / 0.32
45 / rs6762644 / 0.94 (0.82, 1.08) / 0.38
46 / rs6472903 / 1.08 (0.90, 1.29) / 0.40
47 / rs2363956 / 0.95 (0.82, 1.08) / 0.42
48 / rs11249433 / 1.05 (0.92, 1.21) / 0.47
49 / rs2823093 / 1.06 (0.91, 1.23) / 0.47
50 / rs10771399 / 1.08 (0.87, 1.33) / 0.48
51 / rs13387042 / 1.05 (0.91, 1.20) / 0.50
52 / rs2380205 / 0.96 (0.83, 1.09) / 0.50
53 / rs527616 / 1.06 (0.89, 1.26) / 0.53
54 / rs11820646 / 0.96 (0.83, 1.10) / 0.54
55 / rs3760982 / 1.04 (0.91, 1.19) / 0.56
56 / rs12422552 / 0.96 (0.82, 1.11) / 0.58
57 / rs11552449 / 0.95 (0.80, 1.14) / 0.60
58 / rs1550623 / 1.05 (0.87, 1.26) / 0.64
59 / rs132390 / 0.90 (0.57, 1.42) / 0.66
60 / rs6678914 / 0.97 (0.85, 1.11) / 0.67
61 / rs3817198 / 1.03 (0.89, 1.19) / 0.68
62 / rs2588809 / 1.04 (0.87, 1.24) / 0.69
63 / rs13329835 / 0.97 (0.82, 1.15) / 0.73
64 / rs1353747 / 0.96 (0.77, 1.20) / 0.73
65 / rs11814448 / 0.94 (0.61, 1.43) / 0.76
66 / rs17529111 / 1.03 (0.86, 1.23) / 0.76
67 / rs10069690 / 1.02 (0.88, 1.19) / 0.78
68 / rs16857609 / 0.99 (0.85, 1.15) / 0.86
69 / rs204247 / 1.01 (0.88, 1.16) / 0.88
70 / rs865686 / 1.01 (0.88, 1.17) / 0.88
71 / rs4808801 / 1.01 (0.87, 1.17) / 0.90
72 / rs8170 / 0.99 (0.83, 1.18) / 0.91
73 / rs10995190 / 1.01 (0.84, 1.22) / 0.91
74 / rs6504950 / 0.99 (0.85, 1.16) / 0.94
75 / rs1432679 / 1.00 (0.87, 1.14) / 0.97

Supplementary Table S4. Effect estimates for inherited genetic effects of previous breast cancer genome-wide association study risk variants on the risk young-onset breast cancer in families not known to carry deleterious BRCA1/2 mutations (Two Sister Study, 2008-2012)

Rank / SNP / RR (95% CI) / p-value
1
/ rs3803662 / 1.41 (1.21, 1.64) / 6.2 x 10-6
2 / rs12662670 / 1.60 (1.19, 2.15) / 0.002
3 / rs2981579 / 1.25 (1.09, 1.44) / 0.002
4 / rs554219 / 1.34 (1.09, 1.65) / 0.004
5 / rs999737 / 1.26 (1.07, 1.47) / 0.005
6 / rs720475 / 1.23 (1.06, 1.43) / 0.008
7 / rs10941679 / 1.24 (1.05, 1.46) / 0.01
8 / rs13281615 / 1.20 (1.04, 1.38) / 0.01
9 / rs2046210 / 1.20 (1.03, 1.38) / 0.02
10 / rs11199914 / 1.20 (1.03, 1.40) / 0.02
11 / rs10759243 / 1.21 (1.03, 1.43) / 0.02
12 / rs6001930 / 1.28 (1.03, 1.59) / 0.02
13 / rs11780156 / 1.21 (1.02, 1.44) / 0.03
14 / rs75915166 / 1.38 (1.02, 1.86) / 0.03
15 / rs4849887 / 1.26 (1.02, 1.55) / 0.03
16 / rs2943559 / 1.29 (1.01, 1.65) / 0.04
17 / rs2736108 / 1.21 (0.99, 1.46) / 0.06
18 / rs6828523 / 1.23 (0.98, 1.53) / 0.07
19 / rs17356907 / 1.14 (0.98, 1.33) / 0.10
20 / rs12493607 / 1.13 (0.97, 1.31) / 0.11
21 / rs10472076 / 1.12 (0.97, 1.29) / 0.12
22 / rs616488 / 1.12 (0.97, 1.30) / 0.12
23 / rs3903072 / 1.11 (0.97, 1.27) / 0.12
24 / rs4973768 / 1.11 (0.97, 1.27) / 0.14
25 / rs941764 / 1.11 (0.96, 1.28) / 0.17
26 / rs78540526 / 1.23 (0.91, 1.65) / 0.18
27 / rs7726159 / 1.16 (0.94, 1.43) / 0.18
28 / rs11242675 / 1.10 (0.95, 1.26) / 0.19
29 / rs1011970 / 1.12 (0.94, 1.34) / 0.19
30 / rs1292011 / 1.09 (0.95, 1.25) / 0.20
31 / rs7072776 / 0.91 (0.78, 1.05) / 0.20
32 / rs889312 / 1.10 (0.95, 1.27) / 0.21
33 / rs9790517 / 1.11 (0.94, 1.30) / 0.21
34 / rs9693444 / 1.09 (0.94, 1.27) / 0.23
35 / rs1045485 / 1.13 (0.92, 1.39) / 0.25
36 / rs12710696 / 1.08 (0.94, 1.24) / 0.25
37 / rs1436904 / 1.08 (0.94, 1.24) / 0.28
38 / rs6472903 / 1.09 (0.91, 1.30) / 0.35
39 / rs17817449 / 1.07 (0.93, 1.22) / 0.35
40 / rs6762644 / 0.94 (0.82, 1.08) / 0.37
41 / rs2016394 / 1.06 (0.93, 1.22) / 0.37
42 / rs2236007 / 1.07 (0.92, 1.26) / 0.39
43 / rs10995190 / 1.09 (0.90, 1.31) / 0.39
44 / rs11075995 / 0.93 (0.80, 1.09) / 0.39
45 / rs4245739 / 1.07 (0.92, 1.25) / 0.39
46 / rs6504950 / 1.07 (0.91, 1.25) / 0.41
47 / rs10771399 / 1.09 (0.88, 1.34) / 0.42
48 / rs527616 / 1.07 (0.90, 1.28) / 0.44
49 / rs10069690 / 1.06 (0.91, 1.23) / 0.44
50 / rs2363956 / 0.95 (0.83, 1.09) / 0.47
51 / rs3817198 / 1.05 (0.91, 1.21) / 0.48
52 / rs11552449 / 0.94 (0.78, 1.12) / 0.48
53 / rs7904519 / 0.95 (0.83, 1.10) / 0.49
54 / rs11249433 / 1.05 (0.91, 1.21) / 0.52
55 / rs2823093 / 1.05 (0.90, 1.22) / 0.53
56 / rs704010 / 1.04 (0.91, 1.20) / 0.54
57 / rs6678914 / 0.96 (0.84, 1.10) / 0.55
58 / rs12422552 / 0.96 (0.83, 1.12) / 0.62
59 / rs4808801 / 1.04 (0.89, 1.20) / 0.64
60 / rs204247 / 1.03 (0.90, 1.18) / 0.64
61 / rs13387042 / 1.03 (0.90, 1.18) / 0.65
62 / rs2588809 / 0.96 (0.80, 1.15) / 0.66
63 / rs132390 / 1.11 (0.70, 1.75) / 0.66
64 / rs1550623 / 1.04 (0.87, 1.25) / 0.67
65 / rs3760982 / 1.03 (0.90, 1.18) / 0.70
66 / rs11820646 / 0.98 (0.85, 1.13) / 0.76
67 / rs865686 / 1.02 (0.88, 1.18) / 0.79
68 / rs11814448 / 1.06 (0.68, 1.64) / 0.81
69 / rs1432679 / 1.01 (0.88, 1.16) / 0.86
70 / rs16857609 / 1.01 (0.87, 1.18) / 0.86
71 / rs13329835 / 1.01 (0.86, 1.19) / 0.89
72 / rs2380205 / 0.99 (0.87, 1.14) / 0.91
73 / rs1353747 / 1.01 (0.81, 1.26) / 0.92
74 / rs17529111 / 1.00 (0.83, 1.20) / 0.97
75 / rs8170 / 1.00 (0.84, 1.19) / 1.00

Supplementary Table S5. Comparison of p-values for previously established breast cancer susceptibility SNPs: Ahsan et al.[2] versus Shi et al.

SNP / Gene / Ahsan et al.
p-value / Two Sister Study p-value
rs614367 / CCND1 / 1.14x10-8 / 0.003
rs889312 / MAP3K1 / 1.60x10-8 / 0.34
rs2981579 / FGFR2 / 1.94x10-8 / 0.002
rs3803662 / TOX3 / 3.26x10-8 / 7.0x10-6
rs554219 / CCND1 / 1.33x10-7 / 0.02
rs1219648 / FGFR2 / 1.42x10-7 / 0.001
rs2981582 / FGFR2 / 3.13x10-7 / 0.001
rs2046210 / ESR1 / 2.55x10-5 / 0.01
rs12443621 / TOX3 / 1.47x10-4 / 0.006
rs1562430 / ------/ 4.28x10-4 / 0.14
rs3817198 / LSP1 / 5.14x10-4 / 0.45
rs13281615 / POU5F1B/8q24.21 / 6.12x10-4 / 0.04
rs4973768 / SLC4A7 / 7.05x10-4 / 0.07
rs11249433 / FCGR1B/EMBP1 / 0.002 / 0.37
rs75915166 / FGF3 / 0.002 / 0.07
rs13387042 / TNP1 / 0.003 / 0.57
rs527616 / AQP4/18q11.2 / 0.003 / 0.31
rs7904519 / TCF7L2 / 0.004 / 0.39
rs10771399 / PTHLH/12p11.22 / 0.005 / 0.54
rs999737 / RAD51B / 0.007 / 0.003
rs1432679 / EBF1 / 0.007 / 0.84
rs11820646 / BARX2/11q24.3 / 0.008 / 0.44
rs3112612 / TOX3 / 0.008 / 0.05
rs13329835 / CDYL2 / 0.008 / 0.72
rs8051542 / TOX3 / 0.01 / 2.3x10-4
rs4783780 / TOX3 / 0.01 / 0.009
rs720475 / ARHGEF5 / 0.01 / 0.01
rs704010 / ZMIZ1 / 0.01 / 0.39
rs1292011 / TBX3/12q24.21 / 0.01 / 0.13
rs865686 / KLF4/ RPL31P43 / 0.02 / 0.46
rs494406 / CCND1 / 0.02 / 0.30
rs10995190 / ZNF365 / 0.02 / 0.84
rs3757318 / ESR1 / 0.03 / 2.5x10-4
rs2943559 / HNF4G / 0.05 / 0.07
rs16857609 / TNS1/DIRC3 / 0.06 / 0.87
rs204247 / RANBP9 / 0.07 / 0.68
rs10759243 / KLF4/9q31.2 / 0.08 / 0.02
rs2823093 / NRIP1/CYYR1 / 0.10 / 0.49
rs1011970 / CDKN2A/B / 0.11 / 0.13
rs7072776 / MLLT10 / 0.12 / 0.09
rs9790517 / TET2 / 0.12 / 0.55
rs6001930 / MKL1/SGSM3 / 0.14 / 0.02
rs12422552 / ATF7IP/12p13.1 / 0.15 / 0.64
rs11780156 / MIR1208/8q24.21 / 0.15 / 0.04
rs6678914 / LGR6 / 0.15 / 0.65
rs1045485 / CASP8 / 0.15 / 0.20
rs12493607 / TGFBR2 / 0.16 / 0.07
rs616488 / PEX14 / 0.16 / 0.04
rs1436904 / CHST9 / 0.22 / 0.36
rs4808801 / ELL / 0.26 / 0.80
rs11814448 / DNAJC1/10q12.31 / 0.27 / 0.68
rs2380205 / ANKRD16/GDI2 / 0.28 / 0.88
rs4415084 / MRPS30 / 0.29 / 0.08
e
rs3903072 / SNX32/11q13.1 / 0.30 / 0.09
rs6472903 / HNF4G/8q21.11 / 0.32 / 0.40
rs12710696 / OSR1/LINC01376 / 0.34 / 0.20
rs11242675 / FOXQ1 / 0.37 / 0.19
rs10069690 / TERT / 0.39 / 0.67
rs1550623 / CDCA7 / 0.40 / 0.66
rs10472076 / RAB3C/RPL5P15 / 0.41 / 0.13
rs3760982 / KCNN4 / 0.41 / 0.57
rs10941679 / MRPS30 / 0.42 / 0.03
rs9693444 / DUSP4/8p12 / 0.42 / 0.24
rs4245739 / MDM4 / 0.47 / 0.33
rs6504950 / STXBP4 / 0.48 / 0.55
rs6828523 / ADAM29 / 0.49 / 0.05
rs132390 / EMID1 / 0.50 / 0.52
rs1353747 / PDE4D / 0.52 / 0.95
rs7734992 / TERT / 0.62 / 0.78
rs2236007 / PAX9 / 0.63 / 0.40
rs941764 / CCDC88C / 0.64 / 0.10
rs17817449 / FTO / 0.65 / 0.33
rs2016394 / DLX2 / 0.67 / 0.45
rs4849887 / LOC84931/2q14.2 / 0.69 / 0.009
rs11075995 / FTO / 0.69 / 0.25
rs11199914 / FGFR2/10q26.12 / 0.76 / 0.02
rs17530068 / FAM46A / 0.80 / 0.36
rs6762644 / ITPR1 / 0.85 / 0.30
rs17356907 / NTN4/12q22 / 0.89 / 0.08
rs11571833 / BRCA2/N4BP2L1/2 / 0.89 / 0.41
rs2588809 / RAD51B / 0.96 / 0.80
rs11552449 / SYT6/AP4B1 / 0.97 / 0.65
rs3215401 / TERT / NE / 0.03

NE = Not Evaluated; Statistically significant values shown in bold (p<0.05)

Addition of other GWAS-identified SNPs

SNP selection

We identified previous breast cancer GWAS hits using the National Human Genome Research Institute-European Bioinformatics Institute catalog [3] and the National Center for Biotechnology Information Phenotype-Genotype Integrator website[4]. Because young-onset cases make up approximately 20% of all cases[5], any SNPs uniquely associated with young-onset breast cancer might not reach genome-wide significance in a study that included breast cancer of all ages. Therefore, we opted for a less conservative p-value cut-off than is traditional for genome-wide association studies, selecting SNPs with uncorrected p-values <1x10-5 in a published breast cancer GWAS. We also included 12 SNPs Ahsan et al. [2] identified as associated with young-onset breast cancer (p<0.001 after adjusting for the local established risk variant), as well as 9 other SNPs included in their replication analysis of previously-established risk variants.

Four SNPs with minor allele frequencies <1% in our sample were excluded. This resulted in a total of 85 candidate SNPs in our secondary analysis of individual SNP effects (45 genotyped, 40 imputed). The ORs from the original GWAS are reported in Supplementary Table 6. If the risk allele was not specified (21 SNPs), we assumed the minor allele was the risk allele.

Risk score with additional SNPs

To assess the contribution of the additional candidate SNPs, we also examined a risk score that included the 89 SNPs from our secondary selection list. Here, we selected one SNP from each region not already covered by the 77-SNP score(n=44 SNPs) and utilized ORs reported in the original GWAS (Supplementary Table 6).

Results

The main effects for the additional 85candidate SNPs are displayed in Table 6. Twenty of the 85 SNPs were associated with breast cancer risk at =0.05. The SNP with the smallest p-value was rs4784227-A, which is located upstream of TOX3 (RR=1.42, 95% CI:1.23-1.65; p=2.4x10-6). Five other SNPs in this region were also associated with disease risk at <0.05, including rs8051542-A, rs12922061-A, rs12443621-G, rs4783780-C, and rs3112612-A. rs4784227 was in strong linkage disequilibrium with rs3803662, the TOX3 SNP included in the original analysis (r2=0.77), with moderate correlations between the other TOX3 SNPs.

Several SNPs in two other regions- FGFR2 and chromosome 6q25.1 between ESR1 and CCDC170 - were also associated with increased risk of young-onset breast cancer. An imputed SNP, rs9383938-T, was the top-ranked ESR1 SNP and the third-ranked SNP overall (RR=1.60, 95% CI:1.26-2.03; p=6.7x10-6). Other nearby hits included rs3734805-C and rs3757318-A. rs9383938-T, rs3734805-C, and rs3757318-A were moderately correlated with one another (r2=0.50-0.75),and rs3734805 and rs3757318 was both high LD (r2>0.80) with rs12662670, the top ESR1 SNP from the original analysis.

The highest-ranking FGFR2 SNP was rs2981582-A (RR=1.25, 95% CI:1.09-1.44; p=0.001). Other FGFR2 risk variants included rs2981575-G, rs1219648-G, rs1078806-G, and rs2981578-A. All 5were in LD with one another and with rs2981579-A, the FGFR2 SNP included in the original analysis (r2=0.64–0.98).

The remaining 6 SNPs with statistically-significant associations are located in the following loci: CCND1,NTRK3,15q24.3, EIF3FP3, MRPS30,and TERT. Of these, CCND1, MRPS30, and TERT were represented by at least one correlated SNP that had a statistically-significant association in the original analysis.

The joint effect of all 121 SNPs (original 77 + 44 from the secondary list) was slightly more than additive (additive-fit-p=0.03) but less than multiplicative (multiplicative-fit-p=2.2x10-30). However, including the 44-SNP additive score in a model that already included the multiplicative 77-SNP score only minimally increased the strength of the association between the genetic risk score and young-onset breast cancer, with no improvement in the score’s ability to differentiate between case and control sisters (59% of cases had a higher score than her control/pseudo-control sister).

Supplementary Table S6. Relative risks and 95% confidence intervals for the association between secondary candidate SNPs (n=84) and young-onset breast cancer

Rank / SNPa / Gene/ Region / Risk Allele / RAF / RR (95% CI) / p-value / Reported ORb
1 / rs4784227 / TOX3 / A / 0.28 / 1.42 (1.23, 1.65) / 2.4x10-6 / 1.24 [6]
2 / rs9383938 / ESR1 / T / 0.09 / 1.60 (1.26, 2.03) / 6.7x10-5 / 1.28c[7]
3 / rs3734805 / ESR1 / C / 0.08 / 1.59 (1.25, 2.03) / 1.3x10-4 / 1.19c[8]
4 / rs8051542 / TOX3 / A / 0.45 / 1.28 (1.12, 1.46) / 2.3x10-4 / 1.09c[2]
5 / rs3757318 / ESR1 / A / 0.07 / 1.58 (1.23, 2.03) / 2.5x10-4 / 1.30c[9]
6 / rs12922061 / TOX3 / A / 0.26 / 1.30 (1.12, 1.50) / 4.1x10-4 / 1.23c[10]
7 / rs2981582 / FGFR2 / A / 0.42 / 1.25 (1.09, 1.44) / 0.001 / 1.26[11]
8 / rs2981575 / FGFR2 / G / 0.43 / 1.25 (1.09, 1.44) / 0.001 / 1.28[12]
9 / rs1219648 / FGFR2 / G / 0.43 / 1.25 (1.09, 1.43) / 0.001 / 1.20[13]
10 / rs1078806 / FGFR2 / G / 0.44 / 1.24 (1.08, 1.42) / 0.002 / 1.43[14]
11 / rs614367 / CCND1 / A / 0.16 / 1.32 (1.10, 1.60) / 0.003 / 1.15c[9]
12 / rs12443621 / TOX3 / G / 0.49 / 1.21 (1.05, 1.38) / 0.006 / 1.16[2]
13 / rs4783780 / TOX3 / C / 0.49 / 1.19 (1.04, 1.37) / 0.009 / 1.16 [2]
14 / rs3784421 / NTRK3 / A / 0.01 / 2.26 (1.16, 4.41) / 0.01 / NR [15]
15 / rs12906542 / 15q24.3 / G / 0.80 / 1.21 (1.03, 1.43) / 0.02 / 2.00c[14]
16 / rs2981578 / FGFR2 / A / 0.50 / 1.16 (1.02, 1.33) / 0.02 / 1.23 [10]
17 / rs1372878 / EIF3FP3 / A / 0.03 / 1.53 (1.04, 2.25) / 0.03 / NR [15]
18 / rs3215401 / TERT / A / 0.71 / 1.19 (1.01, 1.39) / 0.03 / 1.06c[2]
19 / rs7716600 / MRPS30 / A / 0.22 / 1.18 (1.00, 1.38) / 0.05 / 1.24c[16]
20 / rs3112612 / TOX3 / A / 0.43 / 1.14 (1.00, 1.30) / 0.05 / 1.15 [8]
21 / rs12505080 / NWD2 / C / 0.27 / 1.15 (0.99, 1.33) / 0.06 / 1.22c[13]
22 / rs2180341 / RNF146 / G / 0.24 / 1.15 (0.98, 1.33) / 0.08 / 1.41c[17]
23 / rs4415084 / MRPS30 / A / 0.42 / 1.13 (0.98, 1.30) / 0.08 / 1.17 [8]
24 / rs16886181 / MAP3K1 / C / 0.17 / 1.15 (0.97, 1.37) / 0.10 / 1.26c[8]
25 / rs2048672 / LINC-PINT / G / 0.71 / 0.89 (0.77, 1.03) / 0.11 / 1.11c[18]
26 / rs3750817 / FGFR2 / A / 0.39 / 0.90 (0.78, 1.03) / 0.12 / 1.22 [19]
27 / rs765855 / NXPH1 / G / 0.68 / 0.90 (0.78, 1.03) / 0.12 / 1.14c[20]
28 / rs2290203 / PRC1 / G / 0.79 / 1.13 (0.97, 1.33) / 0.12 / 1.08c[21]
29 / rs16886034 / 5q11 / G / 0.06 / 1.23 (0.94, 1.62) / 0.13 / 1.36c[2]
30 / rs1562430 / 8q24.21 / A / 0.59 / 1.10 (0.97, 1.25) / 0.14 / 1.17c[9]
31 / rs16886165 / MAP3K1 / C / 0.17 / 1.13 (0.95, 1.34) / 0.15 / 1.23 [22]
32 / rs12355688 / ZMIZ1 / T / 0.05 / 0.83 (0.63, 1.09) / 0.17 / 1.24 [23]
33 / rs2229882 / MAP3K1 / T / 0.05 / 1.20 (0.92, 1.58) / 0.18 / 1.45c[2]
34 / rs981782 / HCN1 / C / 0.44 / 0.91 (0.80, 1.04) / 0.18 / 1.04c[11]
35 / rs222949 / CYYR1 / C / 0.02 / 0.70 (0.41, 1.18) / 0.18 / NR [15]
36 / rs10822013 / ZNF365 / T / 0.53 / 1.10 (0.96, 1.25) / 0.19 / 1.12c[18]
37 / rs537626 / 11q13 / C / 0.17 / 1.12 (0.94, 1.34) / 0.19 / 1.29c[2]
38 / rs10411161 / ZNF577 / A / 0.13 / 0.88 (0.73, 1.07) / 0.21 / 1.42c[24]
39 / rs16886113 / 5q11 / C / 0.07 / 1.17 (0.91, 1.50) / 0.21 / 1.35c[2]
40 / rs909116 / TNNT3 / A / 0.53 / 1.08 (0.95, 1.24) / 0.23 / 1.17c[9]
41 / rs9485372 / TAB2 / G / 0.80 / 0.91 (0.77, 1.07) / 0.24 / 1.11c[25]
42 / rs10871290 / GLG1 / G / 0.36 / 1.08 (0.95, 1.24) / 0.25 / NR [26]
43 / rs7726354 / 5q11 / T / 0.06 / 1.17 (0.89, 1.53) / 0.26 / 1.37c[2]
44 / rs10506095 / FGD4 / T / 0.02 / 0.78 (0.51, 1.20) / 0.27 / NR [15]
45 / rs10474352 / ARRDC3 / G / 0.85 / 1.10 (0.92, 1.33) / 0.29 / 1.09c[21]
46 / rs494406 / CCND1 / T / 0.25 / 1.09 (0.93, 1.27) / 0.30 / 1.07c[2]
47 / rs10507679 / RPL32P28 / C / 0.09 / 0.90 (0.72, 1.12) / 0.34 / NR [15]
48 / rs17530068 / 6q14.1 / G / 0.24 / 1.07 (0.92, 1.25) / 0.36 / 1.16c[7]
49 / rs242407 / PELI2 / T / 0.06 / 0.88 (0.67, 1.16) / 0.37 / NR [15]
50 / rs8100241 / ANKLE1 / G / 0.49 / 1.06 (0.93, 1.21) / 0.39 / 1.14c[7]
51 / rs6788895 / SIAH2 / C / 0.98 / 0.85 (0.58, 1.25) / 0.41 / 1.22c[19]
52 / rs458685 / GRIK1 / G / 0.16 / 1.07 (0.90, 1.29) / 0.43 / NR [15]
53 / rs3822625 / 5q11 / G / 0.07 / 1.09 (0.86, 1.40) / 0.47 / 1.36 [2]
54 / rs10505365 / NOV / G / 0.01 / 0.82 (0.48, 1.40) / 0.47 / NR [15]
55 / rs16886364 / 5q11 / G / 0.07 / 1.09 (0.85, 1.40) / 0.48 / 1.36 [2]
56 / rs1017226 / 5q11 / C / 0.07 / 1.09 (0.85, 1.39) / 0.50 / 1.33 [2]
57 / rs16886448 / 5q11 / G / 0.07 / 1.09 (0.85, 1.39) / 0.50 / 1.37 [2]
58 / rs16886397 / 5q11 / G / 0.07 / 1.09 (0.85, 1.39) / 0.50 / 1.36 [2]
59 / rs10490113 / EIF3FP3 / C / 0.10 / 1.08 (0.87, 1.34) / 0.51 / NR [15]
60 / rs2075555 / COL1A1 / T / 0.14 / 0.94 (0.77, 1.15) / 0.54 / NR [15]
61 / rs10489419 / TRIM33 / G / 0.04 / 1.11 (0.78, 1.58) / 0.57 / NR [15]
62 / rs10263639 / STAG3L4 / G / 0.15 / 1.05 (0.88, 1.26) / 0.58 / NR [15]
63 / rs17221259 / 12p13.1 / G / 0.20 / 0.96 (0.82, 1.12) / 0.58 / 1.25 [10]
64 / rs4951011 / ZC3H11A / G / 0.17 / 1.05 (0.88, 1.24) / 0.59 / 1.09c[21]
65 / rs6556756 / MAT2B / C / 0.12 / 1.05 (0.87, 1.28) / 0.61 / NR [15]
66 / rs10510102 / ATE1 / G / 0.19 / 0.96 (0.82, 1.13) / 0.62 / 1.12c[8]
67 / rs1876206 / FBN1 / C / 0.13 / 1.05 (0.87, 1.26) / 0.62 / NR [15]
68 / rs9294818 / BAI3 / G / 0.03 / 1.10 (0.75, 1.61) / 0.64 / NR [15]
69 / rs1154865 / TRHDE / C / 0.24 / 1.04 (0.88, 1.21) / 0.67 / NR [15]
70 / rs13393577 / ERBB4 / C / 0.09 / 0.95 (0.76, 1.19) / 0.67 / 1.53c[27]
71 / rs3799026 / BAI3 / G / 0.03 / 1.08 (0.74, 1.57) / 0.69 / NR [15]
72 / rs1926657 / ABCC4 / A / 0.15 / 0.96 (0.81, 1.15) / 0.69 / NR [15]
73 / rs1978503 / RPL21P126 / G / 0.20 / 0.97 (0.83, 1.15) / 0.75 / NR[15]
74 / rs2290854 / MDM4 / A / 0.30 / 1.02 (0.89, 1.18) / 0.76 / 1.13c[20]
75 / rs4322600 / 14q31.3 / G / 0.75 / 0.98 (0.84, 1.14) / 0.78 / 1.18c[28]
76 / rs7734992 / TERT / C / 0.41 / 1.02 (0.87, 1.21) / 0.78 / 1.05 [2]
77 / rs12655019 / 5q11 / G / 0.10 / 1.03 (0.84, 1.26) / 0.79 / 1.27 [2]
78 / rs1515677 / THSD4 / C / 0.01 / 1.08 (0.68, 1.82) / 0.80 / NR [15]
79 / rs1092913 / ROPN1L / A / 0.12 / 1.03 (0.84, 1.24) / 0.80 / 1.45c[24]
80 / rs10510126 / RPS26P39 / G / 0.89 / 1.02 (0.83, 1.25) / 0.85 / 1.59c[13]
81 / rs2284378 / RALY / T / 0.29 / 0.99 (0.86, 1.14) / 0.90 / 1.16c[7]
82 / rs16882214 / 6p22.3 / C / 0.86 / 0.99 (0.82, 1.20) / 0.92 / 1.43c[14]
83 / rs11196174 / TCF7L2 / G / 0.29 / 1.00 (0.87, 1.16) / 0.95 / 1.13c[20]
84 / rs11082321 / CABLES1 / A / 0.07 / 1.00 (0.77, 1.28) / 0.96 / 1.08c[21]
85 / rs7107217 / RPS27P20 / C / 0.57 / 1.00 (0.87, 1.15) / 0.99 / 1.08 [25]

Abbreviations: CI= Confidence Interval; RR = risk ratio; NR = not reported; RAF= Risk allele frequency

aImputed SNPs are italicized

bOdds ratio (OR) for log-additive model (if available) or co-dominant model. Original ORs<1.00 were transformed to reflect the measured effect of the risk allele.

cAdditional SNPs considered for inclusion in the secondary genetic risk score (n=44) using the effect estimate from the original GWAS. The genetic risk scores included an additional 2 rare SNPs (RAF<1%) not included in the table: rs9383951 (reported OR=1.14[6]) and rs140068132 (reported OR=1.67[29]).

Supplementary References

1.Mavaddat N, Pharoah PD, Michailidou K, Tyrer J, Brook MN, Bolla MK, et al. Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst. 2015;107(5).

2.Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon E, et al. A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age. Cancer Epidemiol Biomarkers Prev. 2014;23(4):658-69.

3.Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acid Research. 2014;42(D1001-D1006).

4.PheGenI: Phenotype-Genotype Integrator. Accessed: October 22, 2015.

5.Breast Cancer Facts and Figures 2011-2012. American Cancer Society; 2011 Accessed: March 23, 2016.

6.Long J, Cai Q, Shu XO, Qu S, Li C, Zheng Y, et al. Identification of a functional genetic variant at 16q12.1 for breast cancer risk: results from the Asia Breast Cancer Consortium. PLoS Genet. 2010;6(6):e1001002.

7.Siddiq A, Couch FJ, Chen GK, Lindstrom S, Eccles D, Millikan RC, et al. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11. Hum Mol Genet. 2012;21(24):5373-84.

8.Fletcher O, Johnson N, Orr N, Hosking FJ, Gibson LJ, Walker K, et al. Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. J Natl Cancer Inst. 2011;103(5):425-35.

9.Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, et al. Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet. 2010;42(6):504-7.

10.Low SK, Takahashi A, Ashikawa K, Inazawa J, Miki Y, Kubo M, et al. Genome-wide association study of breast cancer in the Japanese population. PLoS One. 2013;8(10):e76463.

11.Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087-93.

12.Gaudet MM, Kirchhoff T, Green T, Vijai J, Korn JM, Guiducci C, et al. Common genetic variants and modification of penetrance of BRCA2-associated breast cancer. PLoS Genet. 2010;6(10):e1001183.

13.Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39(7):870-4.

14.Rinella ES, Shao Y, Yackowski L, Pramanik S, Oratz R, Schnabel F, et al. Genetic variants associated with breast cancer risk for Ashkenazi Jewish women with strong family histories but no identifiable BRCA1/2 mutation. Hum Genet. 2013;132(5):523-36.

15.Murabito JM, Rosenberg CL, Finger D, Kreger BE, Levy D, Splansky GL, et al. A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1:S6.

16.Li J, Humphreys K, Darabi H, Rosin G, Hannelius U, Heikkinen T, et al. A genome-wide association scan on estrogen receptor-negative breast cancer. Breast Cancer Res. 2010;12(6):R93.

17.Gold B, Kirchhoff T, Stefanov S, Lautenberger J, Viale A, Garber J, et al. Genome-wide association study provides evidence for a breast cancer risk locus at 6q22.33. Proc Natl Acad Sci U S A. 2008;105(11):4340-5.

18.Cai Q, Long J, Lu W, Qu S, Wen W, Kang D, et al. Genome-wide association study identifies breast cancer risk variant at 10q21.2: results from the Asia Breast Cancer Consortium. Hum Mol Genet. 2011;20(24):4991-9.

19.Elgazzar S, Zembutsu H, Takahashi A, Kubo M, Aki F, Hirata K, et al. A genome-wide association study identifies a genetic variant in the SIAH2 locus associated with hormonal receptor-positive breast cancer in Japanese. J Hum Genet. 2012;57(12):766-71.

20.Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, et al. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genet. 2013;9(3):e1003212.

21.Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet. 2014;46(8):886-90.

22.Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet. 2009;41(5):579-84.

23.Song C, Chen GK, Millikan RC, Ambrosone CB, John EM, Bernstein L, et al. A genome-wide scan for breast cancer risk haplotypes among African American women. PLoS One. 2013;8(2):e57298.

24.Sehrawat B, Sridharan M, Ghosh S, Robson P, Cass CE, Mackey JR, et al. Potential novel candidate polymorphisms identified in genome-wide association study for breast cancer susceptibility. Hum Genet. 2011;130(4):529-37.

25.Long J, Cai Q, Sung H, Shi J, Zhang B, Choi JY, et al. Genome-wide association study in east Asians identifies novel susceptibility loci for breast cancer. PLoS Genet. 2012;8(2):e1002532.

26.Kibriya MG, Jasmine F, Argos M, Andrulis I, John EM, Chang-Claude J, et al. A pilot genome-wide association study of early-onset breast cancer Breast Cancer Res Treat. 2009;114(3):463-7.

27.Kim HC, Lee JY, Sung H, Choi JY, Park SK, Lee KM, et al. A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study. Breast Cancer Res. 2012;14(2):R56.

28.Chen F, Chen GK, Stram DO, Millikan RC, Ambrosone CB, John EM, et al. A genome-wide association study of breast cancer in women of African ancestry. Hum Genet. 2013;132(1):39-48.

29.Fejerman L, Ahmadiyeh N, Hu D, Huntsman S, Beckman KB, Caswell JL, et al. Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25. Nat Commun. 2014;5:5260.