Genetic association studies of complex traits: design and analysis issues

被引:199
作者
Newton-Cheh, C
Hirschhorn, JN
机构
[1] Harvard Univ, Broad Inst, Cambridge, MA 02139 USA
[2] MIT, Cambridge, MA 02139 USA
[3] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA
[4] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA
[5] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
[6] Childrens Hosp, Div Genet, Boston, MA 02115 USA
[7] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA
关键词
association study; complex trait; genetics; genomics; single nucleotide polymorphism; review;
D O I
10.1016/j.mrfmmm.2005.01.006
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Most common diseases and many important quantitative traits are complex genetic traits, with multiple genetic and environmental variables contributing to the observed phenotype. Because of the multi-factorial nature of complex traits, each individual genetic variant generally has only a modest effect, and the interaction of genetic variants with each other or with environmental factors can potentially be quite important in determining the observed phenotype. It remains largely unknown what sort of genetic variants explain inherited variation in complex traits, but recent evidence suggests that common genetic variants will explain at least some of the inherited variation in susceptibility to common disease. Genetic association studies, in which the allele or genotype frequencies at markers are determined in affected individuals and compared with those of controls (either population- or family-based), may be an effective approach to detecting the effects of common variants with modest effects. With the explosion in single nucleotide polymorphism (SNP) discovery and genotyping technologies, large-scale association studies have become feasible, and small-scale association studies have become plentiful. We review the different types of association studies and discuss issues that are important to consider when performing and interpreting association studies of complex genetic traits. Heritable and accurately measured phenotypes, carefully matched large samples, well-chosen genetic markers, and adequate standards in genotyping, analysis, and interpretation are all integral parts of a high-quality association study. (c) 2005 Elsevier B.V. All rights reserved.
引用
收藏
页码:54 / 69
页数:16
相关论文
共 85 条
[1]  
Allison DB, 1997, AM J HUM GENET, V60, P676
[2]   Genomewide scans of complex human diseases:: True linkage is hard to find [J].
Altmüller, J ;
Palmer, LJ ;
Fischer, G ;
Scherb, H ;
Wjst, M .
AMERICAN JOURNAL OF HUMAN GENETICS, 2001, 69 (05) :936-950
[3]   An SNP map of the human genome generated by reduced representation shotgun sequencing [J].
Altshuler, D ;
Pollara, VJ ;
Cowles, CR ;
Van Etten, WJ ;
Baldwin, J ;
Linton, L ;
Lander, ES .
NATURE, 2000, 407 (6803) :513-516
[4]   Patterns of linkage disequilibrium in the human genome [J].
Ardlie, KG ;
Kruglyak, L ;
Seielstad, M .
NATURE REVIEWS GENETICS, 2002, 3 (04) :299-309
[5]   Testing for population subdivision and association in four case-control studies [J].
Ardlie, KG ;
Lunetta, KL ;
Seielstad, M .
AMERICAN JOURNAL OF HUMAN GENETICS, 2002, 71 (02) :304-311
[6]   CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].
BENJAMINI, Y ;
HOCHBERG, Y .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300
[7]   Human type 1 diabetes and the insulin gene: Principles of mapping polygenes [J].
Bennett, ST ;
Todd, JA .
ANNUAL REVIEW OF GENETICS, 1996, 30 :343-370
[8]   Genetic association mapping based on discordant sib pairs: The discordant-alleles test [J].
Boehnke, M ;
Langefeld, CD .
AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (04) :950-961
[9]   Classical twin studies and beyond [J].
Boomsma, D ;
Busjahn, A ;
Peltonen, L .
NATURE REVIEWS GENETICS, 2002, 3 (11) :872-882
[10]   Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease [J].
Botstein, D ;
Risch, N .
NATURE GENETICS, 2003, 33 (Suppl 3) :228-237