Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts

Zhou, Wei; Zhao, Zhangchen; Jb, Nielsen; Fritsche, Lars G.; LeFaive, Jonathon; Taliun, Sarah A. Gagliano; Bi, Wenjian; Gabrielsen, Maiken Elvestad; Daly, Mark J.; Neale, Benjamin M.; Hveem, Kristian; Abecasis, Gonçalo R.; Willer, Cristen J.; Lee, Seunggeun

doi:10.1038/s41588-020-0621-6

Cited by 163 publications

(170 citation statements)

References 38 publications

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“…As single-variant association tests may lack power for rare variants (MAF ≤ 0.5%) and to search for genes with multiple rare protein-altering variants, we performed exome-wide gene-based SKAT-O 38 tests as implemented in SAIGE-GENE 39 to identify rare coding variants associated with TSH. We grouped missense and stop-gain variants with MAF ≤ 0.5% and imputation quality score ≥ 0.8 within each gene and tested 10,071 genes with at least two variants.…”

Section: Resultsmentioning

confidence: 99%

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

et al. 2020

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Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

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Section: Resultsmentioning

confidence: 99%

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

et al. 2020

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“…In total, we observed pLOF variants in 17,142 genes that were defined based on GENCODE v29. We conducted burden tests to examine the association between quantitative lung function traits and gene burden using SAIGE-GENE v0.36.3.3 63 . Gene-level burden was generated by aggregating low frequency pLoF variants weighted by their allele frequencies.…”

Section: Methodsmentioning

confidence: 99%

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

et al. 2020

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Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

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“…Gene-based SKAT-O tests. The exome-wide gene-based SKAT-O tests were performed using SAIGE-GENE v36 23 for all 9 liver traits based on the TOPMedimputed HUNT data. Missense and stop-gain variants annotated by ANNOVAR 42 with MAF ≤ 0.005 were included.…”

Section: Methodsmentioning

confidence: 99%

“…Gene-based burden results are, in contrast to single variant tests, independent of nearby signals and may point to the functional gene in a region. To identify genes functionally involved in the 9 liver-related blood traits, we performed gene-based burden tests using SKAT-O as implemented in SAIGE-GENE 23 . We included all protein-altering variants with frequency below 0.5% in the HUNT dataset.…”

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confidence: 99%

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

Rom

Surakka

et al. 2020

Nat Commun

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Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.

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Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts

Cited by 163 publications

References 38 publications

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease

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