Europe PMC Funders GroupAuthor Manuscript
Nat Genet. Author manuscript; available in PMC 2009 May 01.
Published in final edited form as:
Nat Genet. 2008 November ; 40(11): 1282–1284. doi:10.1038/ng.255.

Europe PMC Funders Author Manuscripts

Male-pattern baldness susceptibility locus at 20p11
J Brent Richards1,2, Xin Yuan3, Frank Geller4, Dawn Waterworth3, Veronique Bataille1,
Daniel Glass1, Kijoung Song3, Gerard Waeber5, Peter Vollenweider5, Katja K H Aben6,7,
Lambertus A Kiemeney8,9, Bragi Walters4, Nicole Soranzo1,10, Unnur Thorsteinsdottir4,Augustine Kong4, Thorunn Rafnar4, Panos Deloukas10, Patrick Sulem4, Hreinn
Stefansson4, Kari Stefansson4, Tim D Spector1,11, and Vincent Mooser3,11
1Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1

7EH, UK 2Department of Medicine, Jewish General Hospital, Faculty of Medicine, McGill
University, Montréal, Québec H3T 1E2, Canada 3Genetics Division, GlaxoSmithKline, King ofPrussia, Pennsylvania 19406, USA 4deCODE Genetics, Reykjavik 101, Iceland 5Department ofInternal Medicine, CHUV University Hospital, Lausanne 1011, Switzerland 6ComprehensiveCancer Center IKO, Radboud University Nijmegen Medical Center, Nijmegen 6501 BG, TheNetherlands 7Department of Epidemiology and Biostatistics, Radboud University Nijmegen
Medical Center, Nijmegen 6500 HB, The Netherlands 8Department of Epidemiology andBiostatistics, Radboud University Nijmegen Medical Center, Nijmegen 6500 HB, The Netherlands
9Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen 6525 GA, TheNetherlands 10Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB101SA, UKAbstract
Europe PMC Funders Author Manuscripts

We conducted a genome-wide association study for androgenic alopecia in 1,125 men andidentified a newly associated locus at chromosome 20p11.22, confirmed in three independentcohorts (n = 1,650; OR = 1.60, P = 1.1 × 10−14 for rs1160312). The one man in seven who harbors
risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased
odds of androgenic alopecia (OR = 7.12, P = 3.7 × 10−15).
Androgenic alopecia is a common disorder affecting 40% of adult men and women1. Menand women with hair loss experience negative body-image perceptions2. Moreover, themechanisms involved in androgenic alopecia may influence common medical disorders,such as coronary heart disease and metabolic syndrome3. Underscoring the social© 2008 Nature Publishing Group
Correspondence should be addressed to T.D.S. (tim.spector@kcl.ac.uk)..
11These authors contributed equally to this work.
AUTHOR CONTRIBUTIONS
V.M., P.V., G.W. and D.W. designed and implemented the CoLaus Study and the primary nested male-pattern baldness study. J.B.R.,
F.G., L.A.K., H.S., K. Stefansson, T.D.S. and V.M. designed the final study with appropriate replication datasets. J.B.R., X.Y., F.G.,
D.W., K. Song and V.M. analyzed the data. J.B.R., V.B., D.G., G.W., P.V., D.W., K.K.H.A., L.A.K., B.W., U.T., A.K., T.R., P.S.,
T.D.S. and V.M. contributed to data collection and phenotype definitions. V.B., G.W., T.D.S. and V.M. obtained funding. N.S. andP.D. performed genotyping for the women from the TwinsUK cohort. J.B.R. wrote the first draft of the paper and all authors madeimportant contributions to the final version of the paper.
COMPETING INTERESTS STATEMENT
The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/.
Published online at http://www.nature.com/naturegenetics/
Reprints and permissions information is available online at Published online at http://npg.nature.com/reprintsandpermissions/
Note: Supplementary information is available on the Nature Genetics website.

Richards et al.

Page 2

implications of baldness, global annual sales of a medical therapy for male-pattern baldness
recently surpassed $405 million (Merck Financial Disclosures, Fourth Quarter 2007).

Europe PMC Funders Author Manuscripts

Androgenic alopecia is a highly heritable condition, with heritability estimates of over
80%4. Genetic variants in, or in proximity to, the AR (androgen receptor) gene have beenpreviously associated with male-pattern baldness5-9. However, as the inheritance pattern of
this trait seems to be polygenic, we undertook a two-stage genome-wide association (GWA)
study for androgenic alopecia.
We carried out an extreme discordant case-control GWA scan for androgenic alopecia
nested within the CoLaus population-based study in Lausanne, Switzerland10. A total of
578 male individuals with early-onset alopecia were compared with 547 male control
individuals without alopecia (Supplementary Methods online). In the second stage, wesought replication in independent samples from the UK, Iceland and The Netherlands. The
UK cohort comprised 453 men (176 affected individuals) from a population-based sample ofBritish twins; 1,308 women (95 affected individuals) from this sample were also assessed
for hair loss. The Dutch cohort comprised 463 men (147 affected individuals) previously
diagnosed with prostate cancer and also assessed for androgenic alopecia. The Icelandicstudy included 734 Icelandic men (536 affected individuals) and 878 Icelandic women (397affected individuals). The overall sample size thus comprised 4,961 individuals.
The GWA study (Supplementary Fig. 1 online) was done using the Affymetrix GeneChip
Human Mapping 500K array in the CoLaus cohort. All SNPs from this GWA study with a Pvalue ≤ 10−5 were from two loci (Supplementary Fig. 2 online). We confirmed theimportance of the previously described AR gene5-9 (OR for lead SNP rs6625163[A] = 3.30
(2.31-4.71), P = 5.0 × 10−11). We also located a new susceptibility locus on chromosome
20p11.22 (OR = 1.79 (1.49-2.15), P = 3.2 × 10−10 for rs1160312[A] and OR = 1.80
(1.49-2.16), P = 3.5 × 10−10 for rs913063[T]; the r2 between rs1160312 and rs913063 was
1.0; Table 1). These SNPs are located over 350 kb distant to the nearest annotated gene,
PAX1.

Europe PMC Funders Author Manuscripts

This same risk allele at rs1160312, rs1160312[A], was associated with an increased risk ofandrogenic alopecia in the TwinsUK cohort (OR = 1.68 (1.22-2.33), P = 2.0 × 10−3), hairloss in men in the Icelandic cohort (OR = 1.41 (1.10-1.79), P = 6.1 × 10−3) and androgenic
alopecia in the Dutch cohort (OR = 1.40 (1.06-1.85), P = 0.018). In a combined analysis of
all male cases and controls, the risk allele was strongly associated with hair loss (OR = 1.60
(1.42-1.80), P = 1.1 × 10−14). In addition, the same risk allele was associated with hair loss
in women (OR = 1.24 (1.05-1.47), P = 0.012) for combined data from Icelandic andTwinsUK women (OR = 1.29 (1.05-1.57), P = 0.01 for Icelandic women; OR = 1.13(0.82-1.56), P = 0.45 for women from the TwinsUK cohort).
We found that 14% of men harbored at least one risk allele at both 20p11.22 and the AR
gene and that this was associated with a markedly increased risk of androgenic alopecia (OR= 7.12 (4.34-11.68), P = 3.7 × 10−15) in the CoLaus cohort. We observed no significant
statistical interaction between the two loci. The variance in androgenic alopecia explainedby the presence of at least one risk allele at both loci was 13.7%. Using all men from thepopulation-based CoLaus study who did not meet case or control definitions and who were
not included in the GWA scan (n = 940), we found that the ability of these two risk alleles toexclude the development of androgenic alopecia was high, but lacked specificity (negative
predictive value = 96.5%, positive predictive value = 12.2%, sensitivity = 98.2%, specificity= 6.6%).

Nat Genet. Author manuscript; available in PMC 2009 May 01.

Richards et al.

Page 3

The rs1160312 SNP lies between PAX1 and FOXA2 on chromosome 20. It is not
immediately clear how this gene might affect androgenic alopecia. Although rs1160312 isover 350 kb away from both genes, it remains possible that this SNP (or another variant inlinkage disequilibrium with it) may influence the expression of either transcript throughlong-range control, as has been demonstrated for other genes involved in development11.
How these variants affect disease outcomes deserves further investigation.

Europe PMC Funders Author Manuscripts

The fact that, despite a relatively small number of subjects, rs1160312 had a genome-wide
significant association with androgenic alopecia in the discovery cohort alone and several
other SNPs within the LD block bearing rs1160312 were associated with androgenic
alopecia (Fig. 1) reflects the strength of the extreme discordant age-based case-control
definitions. The phenotype from the Icelandic and the female TwinsUK cohorts was derived
from self-reported hair loss, without the use of matching diagrams. Although this phenotype
definition is less precise than that derived using diagram-matching techniques, which havebeen previously validated12, the association for males was replicated in Iceland and theresults for females are consistent between the cohorts. However, it is necessary toinvestigate the association for female hair loss in larger and carefully phenotyped cohorts.
Even though the definition of hair loss and the method of sampling differed between the four
study groups, the fact that the association was observed in all groups underscores thegeneralizability of our findings to other European populations. We also note that, as in anyGWA study, the identified variant is likely to be in linkage disequilibrium with the causal
SNP.

Europe PMC Funders Author Manuscripts

These results may have clinical significance. Androgenic alopecia is a disease of
considerable social concern and the scalp is one of the few areas that are directly accessible
by liposome–DNA mixtures13; this method has been demonstrated to result in hair-follicletransfection14. Therefore, if a variant at 20p11.22 influences expression of a transcript, suchas PAX1 or FOXA2, then manipulation of this pathway may lead to a target for genetherapy. However, demonstration of an influence of the chromosome 20p11.22 locus ontranscription of either gene requires further investigation. The relatively high prevalence andmagnitude of risk attributed to the risk alleles at both AR and 20p11.22 loci suggests thatthese markers may assist in the identification of groups of men at high risk for androgenic
alopecia, and the absence of these risk alleles can be helpful in excluding its development.
In summary, we report a replicated GWA study for androgenic alopecia providing evidence
from four distinct European populations for a newly associated locus that influences acommon disorder of social importance. The risk alleles at this newly identified locus and AR
are common in Europeans and impart a relatively large risk for androgenic alopecia. Given
the feasibility of gene therapy in human follicles, our results may point to an intriguing new
potential target for the treatment of hair loss.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
We wish to acknowledge the cooperation and dedication of the study participants and the personnel at therecruitment centers and core facilities. We would like to acknowledge the genotyping contributions of D. Smythand J. Todd. This study was funded in part by GlaxoSmithKline; deCODE Genetics; the Wellcome Trust; NIHR
Biomedical Research Centre (grant to Guys’ and St. Thomas’ Hospitals and King’s College London); the Chronic
Disease Research Foundation; the Canadian Institutes of Health Research (J.B.R.) and the Sixth Framework
Program of the EU contract number 018827 (Polygene).

Nat Genet. Author manuscript; available in PMC 2009 May 01.

Richards et al.

Page 4References

Europe PMC Funders Author Manuscripts

1. Olsen, E. Disorders of hair growth: Diagnosis and Treatment. McGraw-Hill; New York: 1994. p.
257
2. Cash TF, Price VH, Savin RC. J. Am. Acad. Dermatol. 1993; 29:568–575. [PubMed: 8408792]
3. Lo JC, et al. J. Clin. Endocrinol. Metab. 2006; 91:1357–1363. [PubMed: 16434451]
4. Nyholt DR, Gillespie NA, Heath AC, Martin NG. J. Invest. Dermatol. 2003; 121:1561–1564.
[PubMed: 14675213]
5. Ellis JA, Stebbing M, Harrap SB. J. Invest. Dermatol. 2001; 116:452–455. [PubMed: 11231320]
6. Hayes VM, et al. Cancer Epidemiol. Biomarkers Prev. 2005; 14:993–996. [PubMed: 15824176]
7. Hillmer AM, et al. Am. J. Hum. Genet. 2005; 77:140–148. [PubMed: 15902657]
8. Levy-Nissenbaum E, Bar-Natan M, Frydman M, Pras E. Eur. J. Dermatol. 2005; 15:339–340.
[PubMed: 16172040]
9. Prodi DA, et al. J. Invest. Dermatol. 2008; 128:2268–2270. [PubMed: 18385763]
10. Sandhu MS, et al. Lancet. 2008; 371:483–491. [PubMed: 18262040]
11. Kleinjan DA, van Heyningen V. Am. J. Hum. Genet. 2005; 76:8–32. [PubMed: 15549674]
12. Littman AJ, White E. Ann. Epidemiol. 2005; 15:771–772. [PubMed: 15949955]
13. Li L, Hoffman RM. Nat. Med. 1995; 1:705–706. [PubMed: 7585157]
14. Domashenko A, Gupta S, Cotsarelis G. Nat. Biotechnol. 2000; 18:420–423. [PubMed: 10748523]

Europe PMC Funders Author Manuscripts
Nat Genet. Author manuscript; available in PMC 2009 May 01.

Richards et al.

Page 5

Europe PMC Funders Author Manuscripts
Figure 1.

Europe PMC Funders Author Manuscripts

Association between SNPs near chromosome 20p11.22 and androgenic alopecia. (a) −log (Pvalue) measures for association between SNPs and chromosomal position. (b)Recombination hot spots (HapMap CEPH population, NCBI build 36). (c) Linkage
disequilibrium in GOLD heat map Haploview 4.0 color scheme, CEPH population. The xaxis represents genomic position in Mb (a) and in kb (b,c). All P values are derived from theCoLaus cohort, except that for the lead SNP, rs11603132, which is derived from thecombined P value from the CoLaus, TwinsUK, Icelandic and Dutch cohorts.

Nat Genet. Author manuscript; available in PMC 2009 May 01.

Europe PMC Funders Author Manuscripts

Chr.

20

Markerrs1160312

A/G

Table 1Europe PMC Funders Author Manuscripts

277
198
316
1,338

IcelandicDutch
All men

547

1,437

147

536

176

578

Cases

Sample size
Controls

TwinsUK

CoLaus

Cohort

0.52

0.56

0.45

0.43

Controls

0.60

0.64

0.58

0.57

Cases

Risk-allele frequency

1.60 (1.42-1.80)

1.40 (1.06-1.85)

1.41 (1.10-1.79)

1.68 (1.22-2.33)

1.79 (1.49-2.15)

OR per risk allele (95% CI)

0.018

6.1 × 10−3

2.0 × 10−3

3.2 × 10−10P

1.1 × 10−14

P combined

Summary results for the lead SNP from the 20p11.22 locus for androgenic alopecia in men
Richards et al.
Page 6Nat Genet. Author manuscript; available in PMC 2009 May 01.