GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas

Machiela, Mitchell J.; Huang, Wen‐Yi; Wong, Wendy S. W.; Berndt, Sonja I.; Sampson, Joshua N.; Almeida, Jonas De; Abubakar, Mustapha; Hislop, Jada; Chen, Kai-Ling; Dagnall, Casey; Diaz-Mayoral, Norma; Ferrell, Mary; González, Alex; Hicks, Belynda; Hubbard, Aubrey K.; Hutchinson, Amy; Jiang, Kevin; Jones, Kristine; Liu, Jia; Loftfield, Erikka; Loukissas, Jennifer; Mabie, Jerome; Merkle, Shannon; Miller, Eric A.; Minasian, Lori M.; Nordgren, Ellen; Park, Brian; Pinsky, Paul F.; Riley, Thomas L.; Sandoval, Lorena; Saxena, Neeraj K.; Vogt, Aurélie; Wang, Jiahui; Williams, Craig R.; Wright, Patrick; Yeager, Meredith; Zhu, Bin; Zhu, Claire S.; Chanock, Stephen J.; García‐Closas, Montserrat; Freedman, Neal D.

doi:10.1038/s41597-022-01921-2

Cited by 5 publications

(5 citation statements)

References 18 publications

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“…We leveraged genetic data in a total of 904,524 women from eight biobanks worldwide, including European ancestry participants from FinnGen 23 , Estonian Biobank (EBB) 24 , UK Biobank (UKBB) 25,26 , Breast Cancer Association Consortium (BCAC) 27,28 , Million Veteran Program (MVP) 29,30 , Mass General Brigham Biobank (MGB) 31,32 , and Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) 33 , as well as East Asian ancestry participants from Biobank Japan (BBJ) 34 (Supplementary Table S1). The median (SD) age at sample collection for genotyping ranged from 44 (16.3) for EBB to 67.2 (12.9) for FinnGen.…”

Section: Mosaic Loss Of the X Chromosome In Eight Contributed Biobanksmentioning

confidence: 99%

“…We then examined the associations between each identified mLOX susceptibility locus and the counts of different types of blood cells 47 . Of 35 independent mLOX loci (only considering the lead variant of each locus), 33 were associated with at least one of the nine blood cell count traits examined (P<0.05), suggesting a shared genetic etiology between hematopoiesis and development of detectable mLOX (Figure 3D). Again, the mLOX variants shared with mLOY were among the variants associated with the most number of blood cell traits (5.5 traits average over eight variants) compared with mLOX specific variants (3 traits average over 22 variants).…”

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confidence: 99%

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Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Zhao

Pirinen

et al. 2023

Preprint

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Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in FBXO10 which confer a two-fold increased risk of mLOX. A small fraction of these associations were shared with mosaic Y chromosome loss in men, suggesting different biological processes drive the formation and clonal expansion of sex chromosome missegregation events. Allelic shift analyses identified alleles on the X chromosome which are preferentially retained, demonstrating that variation at many loci across the X chromosome is under cellular selection. A novel polygenic score including 44 independent X chromosome allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Collectively our results support a model where germline variants predispose women to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of subsequent clonal expansion.

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Section: Mosaic Loss Of the X Chromosome In Eight Contributed Biobanksmentioning

confidence: 99%

mentioning

confidence: 99%

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Zhao

Pirinen

et al. 2023

Preprint

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“…In Table 3 , we chose individuals with SNPs genotyped on the Illumina Global Screening Array platform for melanoma (2093 cases), prostate cancer (2012 cases), and pancreatic cancer (578 cases) and 57,501 cancer-free controls in the PLCO GWAS [ 39 ] data. We then chose 50 random samples of controls at each controls/case ratio.…”

Section: Resultsmentioning

confidence: 99%

Increase in power by obtaining 10 or more controls per case when type-1 error is small in large-scale association studies

Katki

Berndt

Machiela

et al. 2023

BMC Med Res Methodol

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Background The rule of thumb that there is little gain in statistical power by obtaining more than 4 controls per case, is based on type-1 error α = 0.05. However, association studies that evaluate thousands or millions of associations use smaller α and may have access to plentiful controls. We investigate power gains, and reductions in p-values, when increasing well beyond 4 controls per case, for small α. Methods We calculate the power, the median expected p-value, and the minimum detectable odds-ratio (OR), as a function of the number of controls/case, as α decreases. Results As α decreases, at each ratio of controls per case, the increase in power is larger than for α = 0.05. For α between 10–6 and 10–9 (typical for thousands or millions of associations), increasing from 4 controls per case to 10–50 controls per case increases power. For example, a study with power = 0.2 (α = 5 × 10–8) with 1 control/case has power = 0.65 with 4 controls/case, but with 10 controls/case has power = 0.78, and with 50 controls/case has power = 0.84. For situations where obtaining more than 4 controls per case provides small increases in power beyond 0.9 (at small α), the expected p-value can decrease by orders-of-magnitude below α. Increasing from 1 to 4 controls/case reduces the minimum detectable OR toward the null by 20.9%, and from 4 to 50 controls/case reduces by an additional 9.7%, a result which applies regardless of α and hence also applies to “regular” α = 0.05 epidemiology. Conclusions At small α, versus 4 controls/case, recruiting 10 or more controls/cases can increase power, reduce the expected p-value by 1–2 orders of magnitude, and meaningfully reduce the minimum detectable OR. These benefits of increasing the controls/case ratio increase as the number of cases increases, although the amount of benefit depends on exposure frequencies and true OR. Provided that controls are comparable to cases, our findings suggest greater sharing of comparable controls in large-scale association studies.

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“…Summary-level data pertaining to the association of SNPs with CRC were obtained from three publicly available GWAS: (1) the FinnGen Study (available at , accessed on 2 May 2023); (2) the PLCO Atlas Project (available at , accessed on 2 May 2023); and (3) the Pan-UK Biobank (available at , accessed on 2 May 2023). Detailed information for these studies was reported in the original publications [ 51 , 52 , 53 ]. CRC cases were identified by: (1) ICD-10 codes C18–C20 in the FinnGen Study; (2) ICD-O-2 codes 180, 182–189, 199, 209, 212, and 218 in the PLCO Atlas; and (3) self-report through verbal interview with a trained nurse in the Pan-UK Biobank [ 51 , 52 , 53 ].…”

Section: Methodsmentioning

confidence: 99%

“…Detailed information for these studies was reported in the original publications [ 51 , 52 , 53 ]. CRC cases were identified by: (1) ICD-10 codes C18–C20 in the FinnGen Study; (2) ICD-O-2 codes 180, 182–189, 199, 209, 212, and 218 in the PLCO Atlas; and (3) self-report through verbal interview with a trained nurse in the Pan-UK Biobank [ 51 , 52 , 53 ]. To minimize population stratification bias, only GWAS results from individuals of European ancestry were included.…”

Section: Methodsmentioning

confidence: 99%

Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Han,

Yao,

Yamazaki

et al. 2024

Nutrients

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Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89–0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89–0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPH’s potential role in CRC prevention.

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GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas

Cited by 5 publications

References 18 publications

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection

Increase in power by obtaining 10 or more controls per case when type-1 error is small in large-scale association studies

Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

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