Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.
Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Margaux F
MF
Keller
Mohamad
M
Saad
Jose
J
Bras
Francesco
F
Bettella
Nayia
N
Nicolaou
Javier
J
Simón-Sánchez
Florian
F
Mittag
Finja
F
Büchel
Manu
M
Sharma
J Raphael
JR
Gibbs
Claudia
C
Schulte
Valentina
V
Moskvina
Alexandra
A
Durr
Peter
P
Holmans
Laura L
LL
Kilarski
Rita
R
Guerreiro
Dena G
DG
Hernandez
Alexis
A
Brice
Pauli
P
Ylikotila
Hreinn
H
Stefánsson
Kari
K
Majamaa
Huw R
HR
Morris
Nigel
N
Williams
Thomas
T
Gasser
Peter
P
Heutink
Nicholas W
NW
Wood
John
J
Hardy
Maria
M
Martinez
Andrew B
AB
Singleton
Michael A
MA
Nalls
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D010300:Parkinson Disease / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D044465:White People / Q000235:genetics