Genetic correlates of the timing of natural menopause: the breast and prostate cancer cohort consortium

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GENETIC CORRELATES OF THE TIMING OF NATURAL MENOPAUSE: THE
BREAST AND PROSTATE CANCER COHORT CONSORTIUM

by
Tao Feng

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(BIOSTATISTICS)

May 2010

Copyright 2010 Tao Feng

ii

Table of Contents

List of Tables iii
Abstract iv
Introduction 1
Materials and Methods 3
Results 5
Discussion 10
Bibliography 13

iii

List of Tables
Table 1: Distribution of characteristics among 2453 eligible subjects, 5
by age at natural menopause

Table 2: Characteristics of SNPs genotyped in GNRH1, GNRHR, and 6
FSHB among participants in the BPC3

Table 3: Odds ratios and 95% Confidence Intervals for association 7
between GNRH1 variants and later age at natural menopause
( ≥55 years) among control participants in the BPC3 nested
breast cancer case-control study

Table 4: Odds ratios and 95% Confidence Intervals for association 8
between GNRHR variants and later age at natural menopause
( ≥55 years) among control participants in the BPC3 nested
breast cancer case-control study

Table 5: Odds ratios and 95% Confidence Intervals for association 9
between FSHB variants and later age at natural menopause
( ≥55 years) among control participants in the BPC3 nested
breast cancer case-control study

iv
Abstract
The timing of natural menopause is an important breast cancer risk factor. Several
epidemiological studies suggest that the timing of natural menopause has a strong genetic
component. We used existing genotype data from BPC3 to investigate the association
between common genetic variation in the form of SNPs in three candidate genes
(GNRH1, GNRHR, FSHB) and the timing of natural menopause. For FSHB, subjects
carrying the heterozygous (CT) genotype (OR, 1.61, 95% CI: 1.15-2.25) of rs601681 had
a nominally statistically significant increased risk of later age at natural menopause in
comparison to the CC genotype. Subjects carrying either the heterozygous (CT)
genotype (OR, 1.74; 95% CI, 1.21-2.50) or the homozygous recessive (TT) genotype
(OR, 1.56; 95% CI, 1.02-2.37) of rs6169 had a nominally statistically significant
increased risk of later age at natural menopause in comparison to the CC genotype. These
findings may highlight an important genetic determinant of menopausal timing.

1
Introduction
Epidemiologic research has firmly established that a later age at natural
menopause is an important breast cancer risk factor. Women who experience a later
natural menopause (at age 55+) have a roughly two-fold increased risk for breast cancer
compared to women with an earlier natural menopause (at age<45) (Trichopoulos,
MacMahon et al. 1972). Although factors such as decreased smoking and increased parity
have been associated with later natural menopause (Kato, Toniolo et al. 1998; Henderson,
Bernstein et al. 2008), estimates of the total variance in age at natural menopause
explained by such factors are low, around 10% (van Noord, Dubas et al. 1997). It was
previously demonstrated that race/ethnicity was a statistically significant independent
predictor of the timing of natural menopause (Henderson, Bernstein et al. 2008). This, in
combination with studies implicating familial factors in age at natural menopause
(Cramer, Xu et al. 1997; Torgerson, Thomas et al. 1997), has spurred serious
consideration of the hypothesis that age at natural menopause is a genetically determined
trait.
Few candidate gene association studies of age at natural menopause have been
performed and thus the genes involved in the timing of menopause remain largely
unknown. One gene that has been examined for possible association with age at natural
menopause in humans is Nos3. Interest in this gene was spurred by mouse studies
implicating it as a likely determinant of age at menopause; however studies in humans
have not supported this hypothesis (Hefler, Worda et al. 2002; Worda, Walch et al. 2004).

2
Biologically, hormones such as gonadotropins play an important role in
determining age at natural menopause (Longcope, Franz et al. 1986). The gonadotropin
pathway is an excellent candidate pathway for genetic association studies of age at
natural menopause because of its role in regulating the hypothalamic-pituitary-ovarian
(HPO) axis, the pacemaker of normal reproductive cycling. Key genes in this pathway
include gonadotropin releasing hormone (GNRH1), gonadotropin releasing hormone
receptor (GNRHR), and follicle stimulating hormone beta (FSHB). GNRH1 codes for
gonadotropin releasing hormone (GNRH), a key regulator of the female reproductive
cycle. GNRH acts through binding to GNRH receptors (GNRHR) on the anterior
pituitary. The GNRHR protein is encoded by the gene GNRHR. FSH is a member of the
pituitary glycoprotein hormone family. Its beta subunit is encoded by FSHB. GNRH1 is
located on chromosome 8, has 3 coding exons, and spans 5.8 kilobases (kb). GNRHR is
located on chromosome 4, has 3 coding exons, and spans 18.7 kb. FSHB is located on
chromosome 11, has 2 coding exons, and spans 4.3 kb.
Given the strong biological rationale for a role of GNRH1, GNRHR and FSHB in
HPO axis regulation, we investigated whether common genetic variation in these genes
was associated with age at natural menopause among women in the Breast and Prostate
Cancer Cohort Consortium (BPC3).

3
Materials and Methods
The current analysis utilized existing genotype data collected by the BPC3. The
BPC3 has been described in detail elsewhere (Hunter, Riboli et al. 2008). In brief,
beginning in 2003, the BPC3 has conducted collaborative association studies of hormone-
related gene variants in the form of single nucleotide polymorphisms (SNPs) and
environmental factors hypothesized to be involved in the development of breast and
prostate cancer. The BPC3 pooled biospecimens from 10 cohorts, including 6,292
prospectively ascertained breast cancer cases and 8,135 controls. Institutional Review
Board approval was obtained from all participating institutions, and informed consent
was obtained from all study participants.
Initially, eligible subjects for the current analysis included 8,135 female control
subjects from the BPC3 nested breast cancer case-control study, which included
participants from the following cohorts: CPS2, EPIC, MEC, MHS, Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial cohort (PLCO), AND WHS. Subjects
were then excluded, in sequence, for the following reasons, premenopausal (n=1,471),
perimenopausal/unknown menopausal status (n=528), and missing age at menopause
(n=228). Among the remaining 5,908 subjects, 2,532 women who experienced an
ovariectomy were also excluded due to the inability to accurately assess whether one or
two ovaries had been removed. Subjects from PLCO were excluded (n=873) since
genotyping for the SNPs of interest was not conducted. Fifty-five additional subjects
were excluded because these subjects had less than 90% genotyping success rate. Thus, a
total of 2,453 subjects were included in the final analytic cohort. Among those 2,453
4
subjects, there were 1,617 whites, 245 Hispanics, 217 African Americans, 233 Asians,
and 141 Native Hawaiians. For purposes of this analysis, women with later age at natural
menopause ( ≥ 55 years) were treated as having a positive outcome and those with earlier
age at natural menopause (<55) were considered to be the reference group.
Briefly, genotyping of GNRH1, GNRHR, FSHB was performed using a
fluorescent 5’ endonuclease assay and the assays were read on the ABI-PRISM 7900
(Applied Biosystems, Foster City, CA, USA). All 13 SNPs had a genotyping success rate
above 95%. Hardy-Weinberg equilibrium for each SNP was tested within each
racial/ethnic group; no deviation from Hardy-Weinberg equilibrium was observed (all p
values > 0.05).
Unconditional multivariable logistic regression using SAS 9.0 (SAS Institute, Inc.,
Cary, North Carolina) was performed to estimate and test the associations between a total
of 13 SNPs in GNRH1, GNRHR, FSH and risk of later age at natural menopause. We
assumed a co-dominant model for all SNPs. A log-additive model was also used to test
for a dose-response effect by unit of additional recessive allele. Odds ratios were
estimated adjusting for race/ethnicity, and subcohort. Additional adjustments were made
for factors previously found to be associated with age at natural menopause including
smoking status, body mass index (BMI), age at menarche, oral contraceptive use, and
total number of full-term pregnancies (Henderson, Bernstein et al. 2008).

Results
Characteristics of the study subjects are presented in Table 1. The age distribution
was similar for the subjects with later and earlier age at natural menopause, as was the
distribution of other covariates, including smoking status, BMI, age at menarche, oral
contraceptive use, and total number of full-term pregnancies.
Table 1. Distribution of characteristics among 2453 eligible subjects, by age at
natural menopause

Earlier age at natural menopause, <55 Later age at natural menopause, ≥55

No. of Participants 2218 235

Mean Age in years (sd) 60.0 (6.6) 63.3 (5.5)

Ethnicity
White 1460 (65.8) 157 (66.8)
Hispanic 232 (10.4) 13 (5.5)
African American 199 (9.0) 18 (7.7)
Asian 203 (9.2) 30 (12.8)
Hawaiian 124 (5.6) 17 (7.2)

Smoking Status (%)
Never smoker 1256 (56.6) 160 (68.1)
Former smoker 614 (27.7) 61 (26.0)
Current smoker 321 (14.5) 13 (5.5)
Missing 27 (1.2) 1 (0.4)

Body Mass Index, in kg/m
2
(%)
<25 943 (42.5) 91(38.7)
25-30 797 (35.9) 92 (39.1)
≥30 462 (20.8) 51 (21.8)
Missing 16 (0.8) 1 (0.4)

Total Number of Full-Term Pregnancies (%)
0 248 (11.2) 23 (9.8)
1 225 (10.2) 28 (11.9)
2 618 (27.9) 62 (26.4)
3 482 (21.7) 54 (23.0)
4 275 (12.4) 34 (14.5)
5 164 (7.4) 21 (8.9)
6+ 167 (7.5) 12 (5.1)
Missing 39 (1.7) 1 (0.4)

5

Table 1, continued

Age at Menarche (%)
<=12 917 (41.3) 89 (37.9)
13-14 945 (42.6) 98 (41.7)
≥15 340 (15.4) 43 (18.3)
Missing 16 (0.7) 5 (2.1)

Cohort Site (%)
CPS2 295 (13.3) 38 (16.2)
EPIC 952 (42.9) 97 (41.3)
MEC 971 (43.8) 100 (42.5)

Oral Contraceptive (OC) use (%)
No 1287 (58.0) 157 (66.8)
Yes 905 (40.8) 75 (31.9)
Missing 26 (1.2) 3 (1.3)

Table 2 illustrates the known properties of the SNPs of interest herein. The
function of some SNPs in GNRHR (rs1843593, and rs2630488) and FSHB (rs601681,
and rs1782508) are unknown. All of the genotyped SNPs in GNRH1 are located in exons,
and one of them (rs6185) was non-synonymous (trp>ser). One SNP (rs13138607 in
GNRHR) is located in the 5’ untranslated region.
Table 2. Characteristics of SNPs genotyped in GNRH1, GNRHR, and FSHB among
participants in the BPC3

SNPs Gene Position
a
Location Chromosome no. Function

rs2709618 GNRH1 25267622 Exon 8 Coding-synon
rs1812594 GNRH1 25287397 Exon 8 Coding-synon
rs6185 GNRH1 25280800 Exon 8 Missense
rs4986942 GNRHR 68619601 Exon 4 Coding-synon
rs10031252 GNRHR 68618191 Intron 4 Intron
rs13138607 GNRHR 68621550 5’-UTR 4 5’-UTR
rs1843593 GNRHR 68598998 Unknown 4 Unknown
rs2630488 GNRHR 68595368 Unknown 4 Unknown
rs3796718 GNRHR 68613181 Intron 4 Intron
rs3822196 GNRHR 68614799 Intron 4 Intron
rs601681 FSHB 30234394 Unknown 11 Unknown
rs6169 FSHB 30255185 Exon 11 Coding-synon
rs1782508 FSHB 30243795 Unknown 11 Unknown

a
SNP positions are based on Dec 2009 (University of California at Santa Cruz human genome version 19)
6

Table 3 presents the results of the investigation of the association between the
three GNRH1 variants and the risk of later age at natural menopause. No association was
apparent between rs2709618, rs1812594, rs6185 and risk of later age at natural
menopause (p>0.05).
Table 3. Odds ratios and 95% Confidence Intervals for association between
GNRH1 variants and later age at natural menopause ( ≥55 years) among control
participants in the BPC3 nested breast cancer case-control study

SNPs Genotype Cases(%) Controls(%) OR
a
(95% CI) P OR
b
(95% CI)

rs2709618 GG 82 (35.19) 775 (35.36) 1.00 (reference) 1.00 (reference)
GA 114 (48.93) 1048 (47.18) 1.03 (0.76-1.39) 0.86 1.03 (0.76-1.40)
AA 37 (15.88) 369 (16.83) 0.96 (0.63-1.47) 0.86 0.96 (0.62-1.47)

rs1812594 TT 150 (65.50) 1398 (65.97) 1.00 (reference) 1.00 (reference)
TC 74 (32.31) 630 (29.73) 1.07 (0.80-1.45) 0.64 1.07 (0.79-1.44)
CC 5 (2.18) 91 (4.29) 0.47 (0.19-1.20) 0.11 0.47 (0.19-1.20)

rs6185 CC 126 (54.55) 1219 (56.25) 1.00 (reference) 1.00 (reference)
CG 83 (35.93) 784 (36.18) 0.94 (0.70-1.27) 0.70 0.95 (0.70-1.28)
GG 22 (9.52) 164 (7.57) 1.09 (0.66-1.82) 0.73 1.03 (0.61-1.73)

a
OR adjusted by race/ethnicity, cohort site
b
OR adjusted by race/ethnicity, cohort site smoking status, BMI, age at menarche, OC use, and total number of full-term pregnancies

Table 4 shows the results of the investigation of the association between the seven
GNRHR variants and the risk of later age at natural menopause. None of the SNPs
displayed a statistically significant association with risk of later age at natural menopause,
although a non-significant decreased risk of later age at natural menopause was observed
for three SNPs (rs2630488, rs3796718, rs3822196). For rs2630488, the GG genotype was
associated with a non-significant decreased risk in comparison to the AA genotype (OR,
0.79; 95% CI, 0.54-1.18). For rs3796718, the TC genotypes (OR, 0.85; 95% CI, 0.64-
1.14) was also associated with a non-significant decreased risk of later age at menopause

7
in comparison to the CC genotype. For rs3822196, both the AG and GG genotypes were
similarly associated with decreased risk (OR, 0.87; 95% CI, 0.65-1.18 and OR, 0.61; 95%
CI, 0.31-1.19, respectively) in comparison to the AA genotype.
Table 4. Odds ratios and 95% Confidence Intervals for association between
GNRHR variants and later age at natural menopause ( ≥55 years) among control
participants in the BPC3 nested breast cancer case-control study

SNPs Genotype Cases(%) Controls(%) OR
a
(95% CI) P OR
b
(95% CI)

rs4986942 GG 199 (85.41) 1848 (84.38) 1.00 (reference) 1.00 (reference)
GA 31 (13.30) 331 (15.11) 0.94 (0.63-1.40) 0.75 0.94 (0.62-1.41)
AA 3 (1.29) 11 (0.50) 3.19 (0.87-11.74) 0.80 3.34 (0.87-12.80)

rs10031252 TT 68 (29.31) 584 (26.85) 1.00 (reference) 1.00 (reference)
TA 101 (43.53) 1050 (48.28) 0.83 (0.60-1.15) 0.26 0.83 (0.60-1.16)
AA 63 (27.16) 541 (24.87) 1.00 (0.69-1.44) 0.99 0.97 (0.67-1.41)

rs13138607 GG 64 (27.59) 604 (27.86) 1.00 (reference) 1.00 (reference)
GA 112 (48.28) 1026 (47.32) 1.03 (0.74-1.43) 0.86 1.04 (0.74-1.45)
AA 56 (24.14) 538 (24.82) 0.97 (0.66-1.43) 0.87 0.96 (0.65-1.42)

rs1843593 TT 171 (73.71) 1567 (72.01) 1.00 (reference) 1.00 (reference)
TC 55 (23.71) 561 (25.78) 0.88 (0.63-1.21) 0.42 0.88 (0.64-1.22)
CC 6 (2.59) 48 (2.21) 1.10 (0.46-2.64) 0.82 1.09 (0.45-2.63)

rs2630488 AA 73 (31.74) 609 (28.09) 1.00 (reference) 1.00 (reference)
AG 110 (47.83) 1036 (47.79) 0.92 (0.67-1.27) 0.62 0.94 (0.68-1.30)
GG 47 (20.43) 523 (24.12) 0.79 (0.54-1.18) 0.25 0.81 (0.54-1.21)

rs3796718 TT 135 (57.94) 1156 (53.49) 1.00 (reference) 1.00 (reference)
TC 81 (34.76) 835 (38.64) 0.85 (0.64-1.14) 0.28 0.86 (0.64-1.16)
CC 17 (7.30) 170 (7.87) 0.89 (0.52-1.52) 0.67 0.89 (0.52-1.53)

rs3822196 AA 148 (63.79) 1278 (58.92) 1.00 (reference) 1.00 (reference)
AG 74 (31.90) 747 (34.44) 0.87 (0.65-1.18) 0.37 0.89 (0.66-1.20)
GG 10 (4.31) 144 (6.64) 0.61 (0.31-1.19) 0.15 0.61 (0.31-1.19)

a
OR adjusted by race/ethnicity, cohort site

b
OR adjusted by race/ethnicity, cohort site, smoking status, BMI, age at menarche, OC use, and total number of full term pregnancies
(see above for formatting changes)

Table 5 shows the results for tests of association between FSHB variants and the
risk of later age at natural menopause. Subjects carrying the heterozygous (CT) genotype
8
(OR, 1.61, 95% CI: 1.15-2.25) of rs601681 had a nominally statistically significant
increased risk of later age at natural menopause in comparison to the CC genotype.
However, the homozygotes TT of rs601681 did not give the statistically significant
increased risk (OR, 1.33, 95% CI: 0.87-2.02). Subjects carrying either the heterozygous
(CT) genotype (OR, 1.74; 95% CI, 1.21-2.50) or the homozygous recessive (TT)
genotype (OR, 1.56; 95% CI, 1.02-2.37) of rs6169 had a nominally statistically
significant increased risk of later age at natural menopause in comparison to the CC
genotype. No other statistically significant associations were observed. For rs6169, a log
additive model for this SNP was associated with a statistically significant linear trend
(p
trend
= 0.045).
Table 5. Odds ratios and 95% Confidence Intervals for association between FSHB
variants and later age at natural menopause ( ≥55 years) among control participants
in the BPC3 nested breast cancer case-control study

SNPs Genotype Cases(%) Controls(%) OR
a
(95% CI) P OR
b
(95% CI)

rs601681 CC 55 (23.61) 721 (33.21) 1.00 (reference) 1.00 (reference)
CT 130 (55.79) 1017 (46.84) 1.61 (1.15-2.25) 0.01 1.65 (1.18-2.31)
TT 48 (20.60) 433 (19.94) 1.33 (0.87-2.02) 0.19 1.33 (0.87-2.03)

rs6169
c
CC 43 (18.38) 599 (27.48 ) 1.00 (reference) 1.00 (reference)
CT 128 (54.70) 1027 (47.11) 1.74 (1.21-2.50) 0.01 1.81 (1.26-2.61)
TT 63 (26.92) 554 (25.41) 1.56 (1.02-2.37) 0.04 1.57 (1.03-2.40)

rs1782508 GG 126 (53.85) 1023 (47.10) 1.00 (reference) 1.00 (reference)
GC 93 (39.74) 932 (42.91) 0.86 (0.64-1.14) 0.29 0.86 (0.64-1.15)
CC 15 (6.41) 217 (9.99) 0.60 (0.34-1.06) 0.08 0.58 (0.33-1.01)

a
OR adjusted by race/ethnicity, cohort site
b
OR adjusted by race/ethnicity, cohort site, smoking status, BMI, age at menarche, OC use, and total number of full term pregnancies
c
P
trend
for this SNP is: 0.045, with OR for one unit increase is: 1.21 with 95% CI (1.00-1.48).

9
10
Discussion
The broad range of ages at natural menopause, ranging approximately from 40 to
58 years, especially in developed countries (North American Menopause Society, 2002),
remains an interesting topic in the field. Several studies (Cramer, Xu et al. 1997;
Torgerson, Thomas et al. 1997) have identified some factors associated with age at
natural menopause or menopausal status. These studies indicated that women who have a
family history of earlier age at natural menopause are likely to have an earlier age at
natural menopause. In addition, moderate alcohol usage is correlated with a later age at
natural menopause. Our previous paper also indicated that race/ethnicity is an
independent predictor of age at natural menopause (Henderson, Bernstein et al. 2008).
Specifically, compared with non-Latina white, Japanese Americans experienced the latest
age at natural menopause and Non-US-born Latinas had the earliest age at natural
menopause. In addition, previous studies have suggested that age at natural menopause is
likely to be a highly heritable trait (Snieder, MacGregor et al. 1998).
In the current study, genotype data on several biologically relevant candidate
genes in the HPO axis, from female, postmenopausal controls included in the BPC3
nested breast cancer case-control study, were investigated to determine whether common
variants in these genes were associated with age at natural menopause.
For three SNPs in GNRHR, rs2630488, rs3796718 and rs3822196, a non-
statistically significant decreased risk was apparent. One reason for the lack of statistical
significance in the results may be in the method of classification of age at natural
menopause. Later age at natural menopause was defined by an age at menopause older

11
than 55. Earlier age at natural menopause was defined by an age at menopause younger
than 55. The outcome difference by this definition between the two groups is small. Thus,
a series of additional analyses were performed in which later age at natural menopause
was defined in the same manner, while earlier age at natural menopause was defined as
age at natural menopause younger than 50, 45 or 40 years. Results did not differ from
those presented here (data not shown).
Our study suggests that, of the variants examined, those in FSHB appear to be
most strongly associated with age at natural menopause. Rs601681 and rs6169 appear to
have a similar magnitude risk association for later age at natural menopause. In addition,
the SNPs are highly correlated (r=0.89, p<0.0001). If reflecting a true effect, these
results may be explained by several scenarios. For example, one or the other SNP may
have a true risk effect, or both of these SNPs are correlated with a third SNP with a true
risk effect. These results warrant further investigation in larger studies, and, if replicated,
may highlight an important genetic determinant of menopausal timing.
In this study, we have tested 13 SNPs in 3 genes. Using a conservative Bonferroni
adjustment, we should set up the type one error at 0.004 (alpha=0.05/13 tests). None of
our results meets this rigorous criterion. Additional work to perform permutation testing,
a less conservative approach to adjustment for multiple hypothesis testing, on these data
is planned.
Our study indicates that common genetic variation in genes involved in the HPO
axis may be associated with timing of menopause. If confirmed, this study may provide

12
some important clues about prevention of breast cancer. Further biological basic research
on the genes involved is needed to support our findings.

13
Bibliography
Canzian, F., R. Kaaks, et al. (2009). "Genetic polymorphisms of the GNRH1 and GNRHR
genes and risk of breast cancer in the National Cancer Institute Breast and Prostate
Cancer Cohort Consortium (BPC3)." BMC Cancer 9:257.

Cramer, D.W., H. Xu, et al (1995). "Family history as a predictor of early menopause."
Fertil Steril 64(4):740–5.

Hefler, L. A., C. Worda, et al. (2002). "A polymorphism of the Nos3 gene and age at
natural menopause." Fertility & Sterility 78(6): 1184-6.

Henderson, K. D., L. Bernstein, et al. (2008). "Predictors of the Timing of Natural
Menopause in the Multiethnic Cohort Study." American Journal of Epidemiology
167(11):1287-94.

Hunter, D. J., E. Riboli, et al (2005). "A candidate gene approach to searching for low-
penetrance breast and prostate cancer genes." Nat Rev Cancer 5(12): 977-985.

Kato, I., P. Toniolo, et al (1998). "Prospective Study of Factors Influencing the Onset of
Natural Menopause". Journal of Clinical Epidemiology 51(12): 1271-76.

Longcope, C., C. Franz, et al. (1986). "Steroid and gonadotropin levels in women during
the peri-menopausal years." Maturitas 8(3): 189-96.

North American Menopause Society. "Menopause core curriculum study guide."
Cleveland, OH: North American Menopause Society, 2002.

Snieder, H., A. J. MacGregor, et al. (1998). "Genes control the cessation of a woman's
reproductive life: a twin study of hysterectomy and age at menopause." J Clin Endocrinol
Metab 83(6): 1875-80.

Torgerson, D. J., R. E. Thomas, et al. (1997). "Alcohol consumption and age of maternal
menopause are associated with menopause onset." Maturitas 26(1): 21-5.

Trichopoulos, D., B. MacMahon, et al. (1972). "Menopause and breast cancer risk." J
Natl Cancer Inst 48(3): 605-13.

van Noord, P. A., J. S. Dubas, et al. (1997). "Age at natural menopause in a population-
based screening cohort: the role of menarche, fecundity, and lifestyle factors." Fertility &
Sterility 68(1): 95-102.

Worda, C., K. Walch, et al. (2004). "The influence of Nos3 polymorphisms on age at
menarche and natural menopause." Maturitas 49(2): 157-62.

Asset Metadata

Creator Feng, Tao (author)

Core Title Genetic correlates of the timing of natural menopause: the breast and prostate cancer cohort consortium

Contributor Electronically uploaded by the author (provenance)

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Publication Date 04/27/2010

Defense Date 03/24/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag BPC3,case control study,FSHB,genetic correlates,GNRH1,GNRHR,OAI-PMH Harvest,timing of natural menopause

Language English

Advisor Azen, Stanley Paul (committee chair), Bernstein, Leslie (committee member), Henderson, Katherine (committee member), Mack, Wendy J. (committee member)

Creator Email tafeng@coh.org,taof@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m2963

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Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

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Repository Email uscdl@usc.edu

Abstract (if available)

Abstract The timing of natural menopause is an important breast cancer risk factor. Several epidemiological studies suggest that the timing of natural menopause has a strong genetic component. We used existing genotype data from BPC3 to investigate the association between common genetic variation in the form of SNPs in three candidate genes (GNRH1, GNRHR, FSHB) and the timing of natural menopause. For FSHB, subjects carrying the heterozygous (CT) genotype (OR, 1.61, 95% CI: 1.15-2.25) of rs601681 had a nominally statistically significant increased risk of later age at natural menopause in comparison to the CC genotype. Subjects carrying either the heterozygous (CT) genotype (OR, 1.74