METAL: fast and efficient meta-analysis of genomewide association scans

Willer, Cristen J.; Li, Yun; Abecasis, Gonçalo R.

doi:10.1093/bioinformatics/btq340

Cited by 4,484 publications

(4,378 citation statements)

References 13 publications

Supporting

Mentioning

4,364

Contrasting

Unclassified

Order By: Relevance

“…All study‐specific GWAS results were corrected by the genomic inflation factor λ GC if >1. Due to the IGF‐I and IGFBP‐3 assay‐based differences in both effect sizes and variances of measurements across cohorts, a sample size‐weighted z‐score‐based meta‐analysis implemented in METAL (Willer et al ., 2010) was conducted, and the meta‐analysis P ‐values were corrected for genomic inflation. After meta‐analysis, SNPs with a MAF ≤1% were removed from subsequent analyses.…”

Section: Methodsmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

View full text Add to dashboard Cite

SummaryThe growth hormone/insulin‐like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF‐related proteins including IGF‐I and IGF‐binding protein‐3 (IGFBP‐3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF‐I and IGFBP‐3 concentrations (IGF1, IGFBP3,GCKR,TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP‐3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF‐I and IGFBP‐3 concentrations. The IGF‐I‐decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF‐I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF‐I‐ and IGFBP‐3‐associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF‐I and IGFBP‐3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity‐associated loci.

show abstract

Section: Methodsmentioning

confidence: 99%

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Teumer¹,

Qi²,

Nethander³

et al. 2016

Aging Cell

View full text Add to dashboard Cite

show abstract

“…However, sample‐size weights are easier to implement when the variable is measured in different related scales across populations (Willer et al . 2010). In the particular case of our dataset, we obtained almost identical results with both weighting schemes.…”

Section: Discussionmentioning

confidence: 99%

“…(2010), the inverse‐variance approach requires that estimated effect sizes and their variances be in the same units across populations. If a trait in several populations is measured in different scales, all measurements should be transformed into a common scale.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Meta‐analysis of genome‐wide association from genomic prediction models

Rubio

Duarte²,

Bates³

et al. 2015

Animal Genetics

View full text Add to dashboard Cite

SummaryGenome‐wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta‐analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal‐centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population‐level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits.

show abstract

“…Handgrip strength was used as a continuous trait, and the regression results reflect an increase or decrease in strength (kg) per additive allele. Test statistics for genomewide association analysis were combined using METAL (Willer et al ., 2010). Inverse variance‐weighted meta‐analysis was performed using a fixed‐effects model of β‐estimates and standard errors from each cohort.…”

Section: Subjectsmentioning

confidence: 99%

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

et al. 2016

View full text Add to dashboard Cite

SummaryDecline in muscle strength with aging is an important predictor of health trajectory in the elderly. Several factors, including genetics, are proposed contributors to variability in muscle strength. To identify genetic contributors to muscle strength, a meta‐analysis of genomewide association studies of handgrip was conducted. Grip strength was measured using a handheld dynamometer in 27 581 individuals of European descent over 65 years of age from 14 cohort studies. Genomewide association analysis was conducted on ~2.7 million imputed and genotyped variants (SNPs). Replication of the most significant findings was conducted using data from 6393 individuals from three cohorts. GWAS of lower body strength was also characterized in a subset of cohorts. Two genomewide significant (P‐value< 5 × 10−8) and 39 suggestive (P‐value< 5 × 10−5) associations were observed from meta‐analysis of the discovery cohorts. After meta‐analysis with replication cohorts, genomewide significant association was observed for rs752045 on chromosome 8 (β = 0.47, SE = 0.08, P‐value = 5.20 × 10−10). This SNP is mapped to an intergenic region and is located within an accessible chromatin region (DNase hypersensitivity site) in skeletal muscle myotubes differentiated from the human skeletal muscle myoblasts cell line. This locus alters a binding motif of the CCAAT/enhancer‐binding protein‐β (CEBPB) that is implicated in muscle repair mechanisms. GWAS of lower body strength did not yield significant results. A common genetic variant in a chromosomal region that regulates myotube differentiation and muscle repair may contribute to variability in grip strength in the elderly. Further studies are needed to uncover the mechanisms that link this genetic variant with muscle strength.

show abstract

METAL: fast and efficient meta-analysis of genomewide association scans

Cited by 4,484 publications

References 13 publications

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

Meta‐analysis of genome‐wide association from genomic prediction models

GWAS analysis of handgrip and lower body strength in older adults in the CHARGE consortium

Contact Info

Product

Resources

About