Using genetic information from candidate gene and genome-wide association studies in risk prediction for alcohol dependence.
Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk.
Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Jia
J
Yan
Fazil
F
Aliev
Bradley T
BT
Webb
Kenneth S
KS
Kendler
Vernell S
VS
Williamson
Howard J
HJ
Edenberg
Arpana
A
Agrawal
Mark Z
MZ
Kos
Laura
L
Almasy
John I
JI
Nurnberger
Marc A
MA
Schuckit
John R
JR
Kramer
John P
JP
Rice
Samuel
S
Kuperman
Alison M
AM
Goate
Jay A
JA
Tischfield
Bernice
B
Porjesz
Danielle M
DM
Dick
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000437:Alcoholism / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies / Q000379:methods* / Q000706:statistics & numerical data*; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012372:ROC Curve; D015203:Reproducibility of Results; D012306:Risk; D014481:United States; D055815:Young Adult
Clinical validity; genetic risk prediction; polygenic risk score; psychiatric genetic counseling; receiver operating characteristic curve analysis