Parkinson's Disease Genes Do Not Segregate with Breast Cancer Genes' Loci

Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Parkinson’s Disease Genes do not Segregate with Breast

Cancer Genes’ Loci

Efrat Kravitz1,2, Yael Laitman3, Sharon Hassin-Baer1,4, Rivka Inzelberg1,2,4, Eitan Friedman3,4

1 The Parkinson Disease and Movement Disorders Clinic, and Department of Neurology, Sheba

Medical Center, Tel Hashomer, Ramat Gan, Israel 52621

2 The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

52621

3 The Susanne-Levy Gertner Oncogenetics Unit, The Institute of Human Genetics, Sheba Medical

Center, Tel Hashomer, Ramat Gan, 52621 Israel

4 The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Running title: Loci of Parkinson’s disease and breast cancer genes do not segregate

Key words: Allele sharing; Breast cancer; Genetic loci; Parkinson's disease; SNP's

Financial support: No specific funding was available for this study.

Corresponding author:

Prof Eitan Friedman, Director, The Susanne-Levy Gertner Oncogenetics Unit, The Institute of

Human Genetics, Sheba Medical Center, Tel Hashomer, Ramat Gan, 52621, Israel. Email:

[email protected] or [email protected] Telephone: +972-3-5303173 or

+972-52-2891561; Fax: +972-3-535-7308

Disclosure of potential conflict of interest: All authors declare that they have no conflicts of

interest.

Word count: 797

Total number of figures and tables: 2

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Downloaded from cebp.aacrjournals.org on October 2, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 13, 2013; DOI: 10.1158/1055-9965.EPI-13-0472 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Abstract

Background: Breast cancer (BC) and skin cancer rates among Parkinson’s disease (PD)

patients are higher than in non PD cases, and Jewish-Ashkenazi LRRK2*G2019S mutation

carriers have higher BC rates than non-carriers. Since additional PD-predisposition genes are

implicated in the malignant transformation process, we hypothesized that the association

between BC and PD may be related to segregation of BC loci with known PD predisposition

loci.

Methods: Data mining for single nucleotide polymorphisms (SNPs) reportedly associated

with BC in GWAS that localize to chromosomes bearing known PD predisposition loci: PARK7,

PINK1 (chromosome 1); SNCA (chromosome 4); PARK2 (chromosome 6); and LRRK2

(chromosome 12) was carried out.

Results: A total of 188 BC-associated SNPs were identified in 29 eligible manuscripts: 43

SNPs on chromosome 1 (PINK1); 46 SNPs on chromosome 4 (SNCA), 72 SNPs on

chromosome 6 (PARK2) and 27 SNPs on chromosome 12 (LRRK2). No BC-associated SNP was

located at distance<500,000bp from any of the analyzed PD predisposition genes.

Conclusion: The association between BC and the most common genetic-inherited forms of

PD cannot be accounted for by allele co-segregation at the genomic level.

Impact: To elucidate the association between PD and BC a comprehensive approach that

spans beyond a simple genetic association is required.

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Introduction

Breast cancer (BC) is more frequently diagnosed in patients with sporadic (1) and inherited

forms (2) of PD than in the general population, yet the molecular basis for this association

remains elusive. Given the involvement of PD predisposition genes in cell cycle, their

reported functions as oncogenes and tumor suppressor genes (3), and somatic involvement

in BC tumorigenesis (e.g., 4), we hypothesized that the PD-BC association may be attributed

to co-segregation and in linkage disequilibrium of BC and PD predisposition genes. To test

this notion, we performed a focused literature search for single nucleotide polymorphisms

(SNPs) that have been associated with BC predisposition through genome-wide association

studies (GWAS) and assessed if they are overrepresented in chromosomal regions associated

with inherited forms of PD.

Methods

Search Procedure

Database searches were carried out in PubMed (5), GWAS catalog of the National Human

Genome Research Institute (NHGRI) (6), and the publication database of the Breast Cancer

Association Consortium (BCAC) (7), to identify GWAS studies published until July 2012.

Inherited PD Genes and Chromosomal loci

The following PD predisposition loci were targeted: 1) PARK7 (OMIM# 602533), chromosome

1p36.23; 2) PINK1 (OMIM# 608309), chromosome 1p36.12; 3) SNCA (OMIM# 163890),

chromosome 4q22.1; 4) PARK2 (OMIM# 602544), chromosome 6q25.2–q27; 5) LRRK2

(OMIM# 609007); chromosome 12q12.

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Selection Criteria and SNP's

We searched peer-reviewed, English-language publications reporting GWAS analyses on all

pathological types of BC cases and controls of all ethnicities. Publications assessing

interactions between SNPs and other risk factors or BC mortality risk, and candidate gene

based studies were excluded. Only results from GWAS replication stage with SNPs showing

p ≤ 0.05 that localize to one of the four chromosomes of interest were considered. After

removal of duplicates, SNPs located to the chromosomes of interest, were plotted using the

NCBI Sequence Viewer 2.23 tool (8). The distances between each of the genes of interest

and the identified SNPs on the same chromosome were calculated.

Results

Of 194 articles identified, 153 articles did not meet the selection criteria, and 14 did not

report any chromosomally relevant SNP. The 29 articles that met all review criteria are listed

in Table 1. Overall, 188 BC associated SNPs located to one of the four "target chromosomes"

were identified (Table 2): 43 SNPs localize to chromosome 1 (minimal distance from PINK1 =

916,731 bps; minimal distance from PARK7 = 6,096,002 bps); 46 SNPs localize to

chromosome 4 (minimal distance from SNCA = 3,606,769 bps); 72 SNPs localize to

chromosome 6 (minimal distance from PARK2 = 1,654,718 bps); 27 SNPs localize to

chromosome 12 (minimal distance from LRRK2 = 7,186,058 bps). None of the identified BC

associated SNPs were located at genomic distance <500,000 bps from any of the analyzed

PD genes.

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Discussion

No BC-associated SNPs localized in the genomic proximity of PD predisposition genes found

on chromosomes 1, 4, 6, or 12. Thus, the observed increased BC rates in inherited forms of

PD cannot be accounted for by a simple co-segregation and shared genomic loci.

Despite the lack of association at the genomic level between BC SNPs and PD predisposition

genes, other genetic or epigenetic mechanisms may still be operative. If BC results from the

actions of multiple rare alleles, each one with a medium effect on BC risk, then the

methodology used in GWAS would have missed these relatively rare sequence variants. This

explanation seems less likely as there was no association reported between family history of

BC and PD risk in a large US cohort (9). To assess this possibility, a whole exome—or even a

whole genome—dataset of BC and PD cases should be queried, when it becomes available.

Another possible explanation for the BC-PD association may be epigenetic: miRNA’s may be

involved in promoting the expression of BC related genes and concomitantly, repress genes

that are needed for normal dopaminergic function. Indeed, miR-7, which represses α-

synuclein protein levels and protects cells against oxidative stress, also inhibits epithelial-to-

mesenchymal transition and metastasis of BC cells via focal adhesion kinase (FAK) expression

(10). Lastly, the reported association between BC and PD may relate to abnormal estrogen

metabolism. Women have a reduced PD risk compared with age-matched men, a

phenomenon attributed by some researchers to the neuro-protective properties of estrogen

in PD relevant neurons (11). Tamoxifen, a selective estrogen receptor (ER) modulator, given

to patients with ER positive BC, has been reported to increase PD rates (12). Thus, in post-

menopausal women, markedly reduced estrogen synthesis may both increase the risk of PD,

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and promote the expression of estrogen receptor genes in breast tissue to enhance BC risk

of BC. Noteworthy this is a viable speculation that should be viewed as such.

In conclusion, the association between BC and the most common genetic forms of inherited

PD cannot be accounted for by allele co-segregation at the genomic level.

Authors’ contributions

Conception and design: R. Inzelberg, E. Friedman

Development of methodology: E. Kravitz, Y. Laitman, E. Friedman

Acquisition of data: E. Kravitz

Analysis and interpretation of data: E. Kravitz, Y. Laitman, S. Hassin-Baer, R. Inzelberg, E.

Friedman

Writing, review and/or revision of the manuscript: E. Kravitz, Y. Laitman, S. Hassin-Baer, R.

Inzelberg, E. Friedman

Administrative, technical, or material support: E. Kravitz

Study supervision: R. Inzelberg, E. Friedman

Grant support

Not applicable

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Tables

Table 1.

a Population

b b # Reference Title Ethnicity Cases Controls

1 Antoniou AC, et al. Breast Common variants at 12p11, 12q24, 9p21, Varied 10,200 9,531

Cancer Res. 2012; 14(1):R33 9q31.2 and in ZNF365 are associated with

breast cancer risk for BRCA1 and/or BRCA2

mutation carriers

2 Ghoussaini M, et al. Nat Genome-wide association analysis identifies European, Asian ~70,000 ~68,000

Genet. 2012; 44(3):312 three new breast cancer susceptibility loci

3 Long J, et al. PLoS Genet. Genome-wide association study in East Asians East-Asian (Chinese, 19,091 20,606

2012; 8(2):e1002532 identifies novel susceptibility Loci for breast Korean, and Japanese)

cancer

4 Fletcher O, et al. J Natl Novel breast cancer susceptibility locus at Varied (European, West 11,880 12,487

Cancer Inst. 2011; 103(5):425 9q31.2: results of a genome-wide association African, and East Asian)

study

5 Hutter CM, et al. Cancer Replication of breast cancer GWAS African American 316 7,484

Epidemiol Biomarkers Prev. susceptibility loci in the Women's Health

2011; 20(9):1950 Initiative African American SHARe Study

6 Li J, et al. Breast Cancer Res A combined analysis of genome-wide European 2,702 5,726

Treat. 2011; 126(3):717 association studies in breast cancer

7 Loizidou MA, et al. Breast Replication of genome-wide discovered Cypriot 1,109 1,177

Cancer Res Treat. 2011; breast cancer risk loci in the Cypriot

128(1):267 population

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a Population

b b # Reference Title Ethnicity Cases Controls

8 Sehrawat B, et al. Hum Potential novel candidate polymorphisms Canadian 1,501 1,563

Genet. 2011; 130(4):529 identified in genome-wide association study (predominantly

for breast cancer susceptibility Caucasian)

9 Stevens KN, et al. Cancer Common breast cancer susceptibility loci are Caucasian 2,980 4,978

Res. 2011; 71(19):6240 associated with triple-negative breast cancer

10 Antoniou AC, et al. Nat A locus on 19p13 modifies risk of breast North American, 1,193 1,190

Genet. 2010; 42(10):885 cancer in BRCA1 mutation carriers and is European and

associated with hormone receptor-negative Australian

breast cancer in the general population

11 Gaudet MM, et al. PLoS Common genetic variants and modification of European 2,680 2,546

Genet. 2010; 6(10):e1001183 penetrance of BRCA2-associated breast

cancer

12 Long J, et al. PLoS Genet. Identification of a functional genetic variant Chinese, Japanese 12,671 10,339

2010; 6(6):e1001002 at 16q12.1 for breast cancer risk: results from

the Asia Breast Cancer Consortium

13 Stacey SN, et al. PLoS Genet. Ancestry-shift refinement mapping of the Asian, European, and 10,176 13,286

2010; 6(7):e1001029 C6orf97-ESR1 breast cancer susceptibility African

locus

14 Turnbull C, et al. Nat Genet. Genome-wide association study identifies five European 16,235 17,120

2010; 42(6):504 new breast cancer susceptibility loci

15 Walker LC, et al. Breast Evidence for SMAD3 as a modifier of breast North American, 4,035 3,382

Cancer Res. 2010; 12(6):R102 cancer risk in BRCA2 mutation carriers European and

Australian

Page | 10

a Population

b b # Reference Title Ethnicity Cases Controls

16 Wang X, et al. Hum Mol Common variants associated with breast Caucasian 3,030 2,427

Genet. 2010; 19(14):2886 cancer in genome-wide association studies

are modifiers of breast cancer risk in BRCA1

and BRCA2 mutation carriers

17 Ahmed S, at al. Nat Genet. Newly discovered breast cancer susceptibility Predominantly 4,380 4,280

2009; 41(5):585 loci on 3p24 and 17q23.2 European

18 Dunning AM, et al. Hum Mol Association of ESR1 gene tagging SNPs with European >25,000 >25,000

Genet. 2009; 18(6):1131 breast cancer risk

19 Mavaddat N, et al. Cancer Common genetic variation in candidate genes Predominantly 4,470 4,560

Epidemiol Biomarkers Prev. and susceptibility to subtypes of breast Caucasian

2009; 18(1):255 cancer

20 Saetrom P, et al. Cancer Res. A risk variant in an miR-125b binding site in Predominantly 455 1,142

2009; 69(18):7459 BMPR1B is associated with breast cancer Caucasian

pathogenesis

21 Thomas G, et al. Nat Genet. A multistage genome-wide association study European 9,770 10,799

2009; 41(5):579 in breast cancer identifies two new risk alleles

at 1p11.2 and 14q24.1 (RAD51L1)

22 Zheng W, et al. Nat Genet. Genome-wide association study identifies a Chinese 6,531 3,998

2009; 41(3):324 new breast cancer susceptibility locus at

6q25.1

23 Gold B, et al. Proc Natl Acad Genome-wide association study provides Ashkenazi Jews 1,442 1,465

Sci U S A. 2008; 105(11):4340 evidence for a breast cancer risk locus at

6q22.33

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a Population

b b # Reference Title Ethnicity Cases Controls

24 Cox A, et al. Nat Genet. A common coding variant in CASP8 is Predominantly 11,391– 14,753–

2007; 39(3):352 associated with breast cancer risk European, Asian 18,290 22,670

25 Easton DF, et al. Nature. Genome-wide association study identifies European, Asian 26,258 26,894

2007; 447(7148):1087 novel breast cancer susceptibility loci

26 Gaudet MM, et al. Hum Genetic variation in tumor necrosis factor and Caucasian 5,546 5,219

Genet. 2007; 121(3-4): 483 lymphotoxin-alpha (TNF-LTA) and breast

cancer risk

27 Hunter DJ, et al. Nat Genet. A genome-wide association study identifies Predominantly 2,921 3,214

2007; 39(7):870 alleles in FGFR2 associated with risk of Caucasian

sporadic postmenopausal breast cancer

28 Stacey SN, et al. Nat Genet. Common variants on chromosomes 2q35 and European, multiethnic 4,554 17,577

2007; 39(7):865 16q12 confer susceptibility to estrogen

receptor-positive breast cancer

29 Breast Cancer Association Commonly studied single-nucleotide Predominantly >20,000 >20,000

Consortium. J Natl Cancer polymorphisms and breast cancer: results European, Asian

Inst. 2006; 98(19):1382 from the Breast Cancer Association

Consortium

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Table 2.

a b c Chr Gene/Region SNP Chromosomal position p value 1 RIZ1 rs2235515 14,141,344 0.0204 1 ALPL rs3200254 21,894,735 0.038 1 ALPL rs3738097 21,894,816 0.036 1 WNT4 rs2473253 22,538,787 0.023 1 TRIT1 rs17570439 40,324,210 <0.0001 1 MYCL1 rs3134615 40,362,066 <0.0001 1 MAST2 rs4660891 46,319,447 0.004 1 PIK3R3 rs785467 46,521,559 0.019 1 GNG12 rs3766265 68,198,152 <0.0002 1 GNG12 rs3766270 68,215,424 <0.0005 1 DPYD rs12133176 97,706,237 0.0284 1 DPYD rs4950025 97,717,279 0.0121 1 DPYD rs528455 97,749,198 0.0442 1 DPYD rs10875071 97,814,678 0.0013 1 DPYD rs11165845 97,819,405 0.0273 1 DPYD rs12566907 97,862,237 0.0051 1 DPYD rs7548189 97,867,713 <0.0005 1 DPYD rs4434871 97,873,007 0.0066 1 DPYD rs4497250 97,882,933 0.0174 1 DPYD rs4379706 98,322,379 0.0418 1 DPYD rs6677116 98,337,283 0.0409 1 DPYD rs1801265 98,348,885 0.0493 1 COL11A1 rs1451036 103,149,593 0.0082 1 VAV3 rs2494059 108,239,958 0.0448 1 VAV3 rs1332684 108,414,230 0.0469 1 TRIM45 rs1048635 117,654,858 0.0013 1 rs11249433 121,280,613 <0.0001 1 IL6R rs1386821 154,382,049 0.019 1 ARHGEF2 rs1889532 155,951,502 0.032 1 CD1A rs411089 158,224,825 0.0452 1 CD1C rs10797006 158,257,838 0.0286 1 TBX19 rs2075976 168,269,338 0.0565 1 CACNA1E rs3820260 181,638,511 <0.0001 1 PLA2G4A rs6683363 186,927,369 0.0274 1 CR1 rs650877 207,748,793 0.0192 1 CR1 rs11118131 207,761,196 0.0221 1 CR1 rs677066 207,773,991 0.0036 1 CR1 rs6691117 207,782,931 0.0039 1 CR1 rs12034383 207,803,595 0.002 1 rs4546928 222,079,537 0.0095 1 ENAH rs3795443 225,675,003 0.0354

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a b c Chr Gene/Region SNP Chromosomal position p value 1 ENAH rs4653643 225,675,459 0.0063 1 ENAH rs2840967 225,824,028 0.008 1 PARK7 Range: 8,021,714..8,045,342 Strand: plus 1 PINK1 Range: 20,959,948..20,978,004 Strand: plus 4 TACC3 rs1374468 1,724,579 0.04 4 ACOX3 rs747580 8,373,088 0.0321 4 ACOX3 rs2631731 8,429,817 0.0207 4 rs2222309 12,691,840 0.0123 4 LDB2 rs6837118 16,729,576 0.049 4 rs2697705 17,418,921 <0.0001 4 KCNIP4 rs1460475 21,565,822 0.02 4 rs10025483 24,454,338 0.0122 4 rs9884706 32,632,087 <0.0005 4 rs2166278 32,642,222 <0.0006 4 KIAA1239 rs12505080 37,349,340 <0.0001 4 rs7696175 38,820,986 <0.0001 4 SHISA3 rs3109633 42,380,579 0.047 4 TEC rs2352593 48,197,767 0.026 4 FRYL rs6843340 48,619,937 0.0009 4 UGT2B4 rs1389930 70,347,172 0.0488 4 UGT2A1 rs6600793 70,477,984 0.006 4 STE rs3775775 70,718,282 0.0182 4 STE rs3736599 70,725,821 0.0053 4 HNRPDL rs1559949 83,340,605 0.0165 4 HNRPDL rs4285076 83,369,287 0.038 4 MAPK10 rs4403040 87,038,481 <0.0009 4 BMPR1B rs1970801 96,070,525 <0.0002 4 BMPR1B rs1434536 96,075,965 <0.0002 4 BMPR1B rs11097457 96,076,813 <0.0002 4 ADH1B rs1042026 100,228,466 0.0253 4 ADH1C rs698 100,260,789 0.0196 4 MANBA rs2866413 103,557,077 0.05 4 MANBA rs228611 103,561,709 0.0259 4 MANBA rs228614 103,578,637 0.0085 4 MANBA rs228617 103,580,788 0.0047 4 MANBA rs227284 103,607,635 0.0227 4 MANBA rs227368 103,611,845 0.0101 4 MANBA rs223502 103,640,758 0.034 4 MANBA rs223500 103,647,047 0.0248 4 rs9761051 120,013,590 <0.0006 4 LOC644624 rs1433211 124,763,465 0.014 4 rs724950 128,342,120 <0.0001 4 rs2862752 132,285,856 0.0134

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a b c Chr Gene/Region SNP Chromosomal position p value 4 NR3C2 rs16998733 149,337,408 <0.0001 4 rs6837016 155,890,241 0.0004 4 PDGFC rs1816164 157,696,636 0.0475 4 rs581849 159,981,640 0.0385 4 rs2014078 160,019,492 0.0127 4 rs11721955 160,046,565 0.011 4 DDX60L rs13110927 169,299,528 <0.0001 4 SNCA Range: 90,645,250..90,759,447 Strand: minus 6 IRF4 rs12203592 396,321 0.0017 6 rs1265273 4,469,641 <0.0002 6 rs9393089 9,095,364 0.0247 6 PHACTR1 rs9473086 12,957,035 0.0047 6 TPMT rs9367980 18,131,464 0.014 6 THEM2 rs3777663 24,700,235 0.013 6 THEM2 rs9356943 24,709,830 0.029 6 LOC134997 rs9393597 24,973,108 <0.0001 6 LRRC16A rs9467504 25,414,325 <0.0001 6 TNF rs361525 31,543,101 0.008 6 LSM2 rs480092 31,764,899 0.0465 6 BAT8 rs535586 31,860,337 0.0138 6 HLA-DRA rs3129871 32,406,342 0.0147 6 HLA-DRA rs2395182 32,413,317 0.0155 6 TCP11 rs2057537 35,090,279 <0.0005 6 CDKN1A rs3176336 36,648,816 0.003 6 C6orf89 rs9380618 36,853,543 <0.0008 6 rs2799359 46,144,252 <0.0010 6 GFRAL rs12210212 55,202,199 0.019 6 HMGCLL1 rs4072373 55,317,936 0.029 6 rs9454109 67,947,988 0.0178 6 rs6919990 77,384,675 0.0019 6 rs3857481 87,124,569 <0.0001 6 QRSL1 rs12333016 107,099,191 <0.0004 6 CDC40 rs7761436 110,502,831 0.0163 6 FYN rs6914091 112,081,735 0.0077 6 ROS1 rs9401003 117,718,303 <0.0007 6 RNF146 rs2180341 127,600,630 <0.0001 6 RNF146 rs6569479 127,606,588 <0.0001 6 ECHDC1 rs6569480 127,621,748 <0.0001 6 ECHDC1 rs7776136 127,638,348 <0.0001 6 rs11759744 127,708,247 0.0608 6 THEMIS rs9491859 128,064,363 <0.0001 6 VNN2 rs12211125 133,065,049 0.0103 6 rs9485372 149,608,874 <0.0001

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a b c Chr Gene/Region SNP Chromosomal position p value 6 C6orf97 rs3757318 151,914,113 <0.0001 6 C6orf97 rs12662670 151,918,856 <0.0001 6 C6orf97 rs9383932 151,919,720 <0.0003 6 C6orf97 rs1038304 151,933,175 <0.0001 6 C6orf97 rs6929137 151,936,677 0.017 6 C6orf97 rs3734804 151,939,181 0.0014 6 C6orf97 rs3734805 151,939,350 <0.0001 6 C6orf97 rs6932260 151,939,560 <0.0008 6 C6orf97 rs9383589 151,940,260 <0.0001 6 C6orf97 rs10872676 151,943,977 0.0016 6 C6orf97-ESR1 rs12665607 151,946,629 <0.0001 6 C6orf97-ESR1 rs7752591 151,947,068 0.0003 6 C6orf97-ESR1 rs2046210 151,948,366 <0.0001 6 C6orf97-ESR1 rs9397435 151,951,220 <0.0001 6 rs6900157 151,954,127 <0.0001 6 C6orf97-ESR1 rs6930633 151,958,091 0.0504 6 C6orf97-ESR1 rs852003 151,962,202 <0.0002 6 C6orf97-ESR1 rs77275268 151,969,198 0.0074 6 C6orf97-ESR1 rs9383938 151,987,357 <0.0004 6 ESR1 rs3020314 152,270,672 <0.0001 6 ESR1 rs3020377 152,272,398 0.0043 6 ESR1 rs3020390 152,276,458 0.0046 6 ESR1 rs3020317 152,278,741 0.003 6 ESR1 rs3020394 152,279,213 0.0034 6 ESR1 rs3020396 152,279,878 0.0038 6 ESR1 rs3020400 152,282,546 0.0047 6 ESR1 rs3020401 152,283,044 0.0039 6 ESR1 rs1884051 152,283,279 0.0299 6 ESR1 rs1884054 152,291,566 0.0328 6 ESR1 rs9383951 152,295,613 <0.0001 6 ESR1 rs3020405 152,299,953 0.0077 6 ESR1 rs726282 152,302,654 0.0167 6 ESR1 rs3020407 152,307,261 0.0062 6 rs694975 153,189,269 0.034 6 TIAM2 rs9478620 155,513,482 0.0351 6 TIAM2 rs3749870 155,554,351 0.0362 6 SOD2 rs4880 160,113,872 0.056 6 PARK2 Range: 161,768,590..163,148,834 Strand: minus 12 FOXM1 rs2074985 2,978,254 0.034 12 PRMT8 rs10774156 3,664,704 0.0462 12 PRMT8 rs1029766 3,703,500 0.0017 12 FGF23 rs7961824 4,476,217 0.0387 12 MLF2 rs2302371 6,858,126 0.0494

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a b c Chr Gene/Region SNP Chromosomal position p value 12 CDKN1B rs34330 12,870,695 0.012 12 GRIN2B rs2284424 13,988,870 <0.0009 12 rs7313833 28,083,196 <0.0001 12 PTHLH rs10771399 28,155,080 <0.0001 12 FGD4 rs10771973 32,792,974 <0.0002 12 rs12304191 47,949,145 0.0334 12 OR6C74 rs4388990 55,641,295 0.0076 12 RASSF3 rs15958 65,091,314 0.016 12 TMTC2 rs17740709 83,423,340 <0.0001 12 MKRN5 rs1461282 88,186,449 0.0444 12 rs7310517 89,149,235 <0.0006 12 rs10507088 97,879,744 <0.0003 12 GLTP rs7966820 110,302,270 0.0004 12 rs10850145 113,944,129 <0.0001 12 rs1292011 115,836,522 <0.0001 12 rs7955262 116,206,962 <0.0001 12 KSR2 rs12425296 117,987,574 0.042 12 KSR2 rs4766886 118,345,121 0.047 12 CIT rs4766950 120,278,241 0.024 12 AACS rs7307700 125,588,197 0.002 12 rs6489171 127,882,841 <0.0001 12 rs11609565 132,093,024 0.047 12 LRRK2 Range: 40,618,813..40,763,087 Strand: plus

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Table and figure legends

Table 1.

Articles included in this review.

a Population of the entire study, including all stages/population sets

b Number of cases/controls for all population sets

Table 2.

Breast-cancer associated SNPs on chromosomes of interest.

a If applicable

b Actual position for SNP search on map

c Smallest p value of all appearances

Page | 18

Parkinson's Disease Genes do not Segregate with Breast Cancer Genes' Loci

Efrat Kravitz, Yael Laitman, Sharom Behar Hassin, et al.

Cancer Epidemiol Biomarkers Prev Published OnlineFirst June 13, 2013.

Updated version Access the most recent version of this article at: doi:10.1158/1055-9965.EPI-13-0472

Author Author manuscripts have been peer reviewed and accepted for publication but have not yet been Manuscript edited.

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