Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.
Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻⁹-1.01×10⁻¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10⁻⁸⁸]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.
Departments of Medicine, Human Genetics, Epidemiology, and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Rui
R
Li
Felix F
FF
Brockschmidt
Amy K
AK
Kiefer
Hreinn
H
Stefansson
Dale R
DR
Nyholt
Kijoung
K
Song
Sita H
SH
Vermeulen
Stavroula
S
Kanoni
Daniel
D
Glass
Sarah E
SE
Medland
Maria
M
Dimitriou
Dawn
D
Waterworth
Joyce Y
JY
Tung
Frank
F
Geller
Stefanie
S
Heilmann
Axel M
AM
Hillmer
Veronique
V
Bataille
Sibylle
S
Eigelshoven
Sandra
S
Hanneken
Susanne
S
Moebus
Christine
C
Herold
Martin
M
den Heijer
Grant W
GW
Montgomery
Panos
P
Deloukas
Nicholas
N
Eriksson
Andrew C
AC
Heath
Tim
T
Becker
Patrick
P
Sulem
Massimo
M
Mangino
Peter
P
Vollenweider
Tim D
TD
Spector
George
G
Dedoussis
Nicholas G
NG
Martin
Lambertus A
LA
Kiemeney
Vincent
V
Mooser
Kari
K
Stefansson
David A
DA
Hinds
Markus M
MM
Nöthen
J Brent
JB
Richards
D000328:Adult; D000368:Aged; D000483:Alleles; D000505:Alopecia / Q000235:genetics*; D005298:Fertility / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors