Meta-Analysis of Rare Variant Association Tests in Multiethnic Populations

被引:9
作者
Mensah-Ablorh, Akweley [1 ,2 ]
Lindstrom, Sara [1 ,2 ]
Haiman, Christopher A. [3 ,4 ]
Henderson, Brian E. [3 ,4 ]
Le Marchand, Loic [5 ]
Lee, Seunngeun [6 ]
Stram, Daniel O. [3 ,4 ]
Eliassen, A. Heather [1 ,7 ]
Price, Alkes [1 ,2 ,8 ]
Kraft, Peter [1 ,2 ,8 ]
机构
[1] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA
[2] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02215 USA
[3] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA
[4] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA
[5] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96813 USA
[6] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA
[7] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA
[8] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA
关键词
fine mapping; sequencing study design; statistical genetics; study subject selection; multiethnic meta-analysis; BREAST-CANCER; GENETIC ASSOCIATION; COMMON DISEASES; RISK; FRAMEWORK; HETEROGENEITY; STRATEGIES; REVEALS; COHORT; POWER;
D O I
10.1002/gepi.21939
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Several methods have been proposed to increase power in rare variant association testing by aggregating information from individual rare variants (MAF < 0.005). However, how to best combine rare variants across multiple ethnicities and the relative performance of designs using different ethnic sampling fractions remains unknown. In this study, we compare the performance of several statistical approaches for assessing rare variant associations across multiple ethnicities. We also explore how different ethnic sampling fractions perform, including single-ethnicity studies and studies that sample up to four ethnicities. We conducted simulations based on targeted sequencing data from 4,611 women in four ethnicities (African, European, Japanese American, and Latina). As with single-ethnicity studies, burden tests had greater power when all causal rare variants were deleterious, and variance component-based tests had greater power when some causal rare variants were deleterious and some were protective. Multiethnic studies had greater power than single-ethnicity studies at many loci, with inclusion of African Americans providing the largest impact. On average, studies including African Americans had as much as 20% greater power than equivalently sized studies without African Americans. This suggests that association studies between rare variants and complex disease should consider including subjects from multiple ethnicities, with preference given to genetically diverse groups. (C) 2015 Wiley Periodicals, Inc.
引用
收藏
页码:57 / 65
页数:9
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