PASTRY: achieving balanced power for detecting risk and protective minor alleles in meta-analysis of association studies with overlapping subjects.

BACKGROUND: Meta-analysis is a statistical method that combines the results of multiple studies to increase statistical power. When multiple studies participating in a meta-analysis utilize the same public dataset as controls, the summary statistics from these studies become correlated. To solve this challenge, Lin and Sullivan proposed a method to provide an optimal test statistic adjusted for the correlation. This method quickly became the standard practice. However, we identified an unexpected power asymmetry phenomenon in this standard framework. This can lead to unbalanced power for detecting protective minor alleles and risk minor alleles. RESULTS: We found that the power asymmetry of the current framework is mainly due to the errors in approximating the correlation term. We then developed a meta-analysis method based on an accurate correlation estimator, called PASTRY (A method to avoid Power ASymmeTRY). PASTRY outperformed the standard method on both simulated and real datasets in terms of the power symmetry. CONCLUSIONS: Our findings suggest that PASTRY can help to alleviate the power asymmetry problem. PASTRY is available at https://github.com/hanlab-SNU/PASTRY .

Amino acid position 37 of HLA-DRß1 affects susceptibility to Crohn's disease in Asians.

Crohn's disease (CD) and ulcerative colitis (UC) are the major types of chronic inflammatory bowel disease (IBD) characterized by recurring episodes of inflammation of the gastrointestinal tract. Although it is well established that human leukocyte antigen (HLA) is a major risk factor for IBD, it is yet to be determined which HLA alleles or amino acids drive the risks of CD and UC in Asians. To define the roles of HLA for IBD in Asians, we fine-mapped HLA in 12 568 individuals from Korea and Japan (3294 patients with CD, 1522 patients with UC and 7752 controls). We identified that the amino acid position 37 of HLA-DRß1 plays a key role in the susceptibility to CD (presence of serine being protective, P = 3.6 × 10-67, OR = 0.48 [0.45-0.52]). For UC, we confirmed the known association of the haplotype spanning HLA-C*12:02, HLA-B*52:01 and HLA-DRB1*1502 (P = 1.2 × 10-28, OR = 4.01 [3.14-5.12]).

FOLD: a method to optimize power in meta-analysis of genetic association studies with overlapping subjects.

MOTIVATION: In genetic association studies, meta-analyses are widely used to increase the statistical power by aggregating information from multiple studies. In meta-analyses, participating studies often share the same individuals due to the shared use of publicly available control data or accidental recruiting of the same subjects. As such overlapping can inflate false positive rate, overlapping subjects are traditionally split in the studies prior to meta-analysis, which requires access to genotype data and is not always possible. Fortunately, recently developed meta-analysis methods can systematically account for overlapping subjects at the summary statistics level. RESULTS: We identify and report a phenomenon that these methods for overlapping subjects can yield low power. For instance, in our simulation involving a meta-analysis of five studies that share 20% of individuals, whereas the traditional splitting method achieved 80% power, none of the new methods exceeded 32% power. We found that this low power resulted from the unaccounted differences between shared and unshared individuals in terms of their contributions towards the final statistic. Here, we propose an optimal summary-statistic-based method termed as FOLD that increases the power of meta-analysis involving studies with overlapping subjects. AVAILABILITY AND IMPLEMENTATION: Our method is available at http://software.buhmhan.com/FOLD. CONTACT: mail: buhm.han@amc.seoul.kr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.