Search Results (5)

In genomic studies, univariate analysis is commonly used to discover susceptible variants. It applies univariate regression for each variant and tests the significance of the regression coefficient or slope parameter. This strategy, however, may miss signals that are jointly detectable with other variants. Multivariate analysis is another popular approach, which tests grouped variants with a predefined group, e.g., based on a gene, pathway, or physical location. However, the power will be diminished if the modeling assumption is not suited to the data. Therefore, data-adaptive testing that relies on fewer modeling assumptions is preferable. Possible approaches include a data-adaptive test proposed by Ueki (2021), which applies to various data-adaptive regression models using a generalization of Yanai’s generalized coefficient of determination. While several regression models are possible choices for the data-adaptive test, this paper focuses on the fused lasso that can count for the effect of adjacent variants and investigates its performance through comparison with other existing tests. Simulation studies demonstrate that the test using fused lasso has a high power compared to the existing tests including the univariate regression test, saturated regression test, SKAT (sequence kernel association test), burden test, SKAT-O (optimized sequence kernel association test), and the tests using lasso, ridge, and elastic net when assuming a similar effect of adjacent variants. Full article

Homologous recombination deficiency (HRD) has been used to predict both cancer prognosis and the response to DNA-damaging therapies in many cancer types. HRD has diverse manifestations in different cancers and even in different populations. Many screening strategies have been designed for detecting the sensitivity of a patient’s HRD status to targeted therapies. However, these approaches suffer from low sensitivity, and are not specific to each cancer type and population group. Therefore, identifying race-specific and targetable HRD-related genes is of clinical importance. Here, we conducted analyses using genomic sequencing data that was generated by the Pan-Cancer Atlas. Collapsing non-synonymous variants with functional damage to HRD-related genes, we analyzed the association between these genes and race within cancer types using the optimal sequencing kernel association test (SKAT-O). We have identified race-specific mutational patterns of curated HRD-related genes across cancers. Overall, more significant mutation sites were found in ATM, BRCA2, POLE, and TOP2B in both the ‘White’ and ‘Asian’ populations, whereas PTEN, EGFG, and RIF1 mutations were observed in both the ‘White’ and ‘African American/Black’ populations. Furthermore, supported by pathogenic tendency databases and previous reports, in the ‘African American/Black’ population, several associations, including BLM with breast invasive carcinoma, ERCC5 with ovarian serous cystadenocarcinoma, as well as PTEN with stomach adenocarcinoma, were newly described here. Although several HRD-related genes are common across cancers, many of them were found to be specific to race. Further studies, using a larger cohort of diverse populations, are necessary to identify HRD-related genes that are specific to race, for guiding gene testing methods. Full article

Severe periodontitis is prevalent in Down syndrome (DS). This study aimed to identify genetic variations associated with periodontitis in individuals with DS. The study group was distributed into DS patients with periodontitis (n = 50) and DS patients with healthy periodontium (n = 36). All samples were genotyped with the “Axiom Spanish Biobank” array, which contains 757,836 markers. An association analysis at the individual marker level using logistic regression, as well as at the gene level applying the sequence kernel association test (SKAT) was performed. The most significant genes were included in a pathway analysis using the free DAVID software. C12orf74 (rs4315121, p = 9.85 × 10⁻⁵, OR = 8.84), LOC101930064 (rs4814890, p = 9.61 × 10⁻⁵, OR = 0.13), KBTBD12 (rs1549874, p = 8.27 × 10⁻⁵, OR = 0.08), PIWIL1 (rs11060842, p = 7.82 × 10⁻⁵, OR = 9.05) and C16orf82 (rs62030877, p = 8.92 × 10⁻⁵, OR = 0.14) showed a higher probability in the individual analysis. The analysis at the gene level highlighted PIWIL, MIR9-2, LHCGR, TPR and BCR. At the signaling pathway level, PI3K-Akt, long-term depression and FoxO achieved nominal significance (p = 1.3 × 10⁻², p = 5.1 × 10⁻³, p = 1.2 × 10⁻², respectively). In summary, various metabolic pathways are involved in the pathogenesis of periodontitis in DS, including PI3K-Akt, which regulates cell proliferation and inflammatory response. Full article

Because studies of rare variant effects on gene expression have limited power, we investigated set-based methods to identify rare expression quantitative trait loci (eQTL) related to Alzheimer disease (AD). Gene-level and pathway-level cis rare-eQTL mapping was performed genome-wide using gene expression data derived from blood donated by 713 Alzheimer’s Disease Neuroimaging Initiative participants and from brain tissues donated by 475 Religious Orders Study/Memory and Aging Project participants. The association of gene or pathway expression with a set of all cis potentially regulatory low-frequency and rare variants within 1 Mb of genes was evaluated using SKAT-O. A total of 65 genes expressed in the brain were significant targets for rare expression single nucleotide polymorphisms (eSNPs) among which 17% (11/65) included established AD genes HLA-DRB1 and HLA-DRB5. In the blood, 307 genes were significant targets for rare eSNPs. In the blood and the brain, GNMT, LDHC, RBPMS2, DUS2, and HP were targets for significant eSNPs. Pathway enrichment analysis revealed significant pathways in the brain (n = 9) and blood (n = 16). Pathways for apoptosis signaling, cholecystokinin receptor (CCKR) signaling, and inflammation mediated by chemokine and cytokine signaling were common to both tissues. Significant rare eQTLs in inflammation pathways included five genes in the blood (ALOX5AP, CXCR2, FPR2, GRB2, IFNAR1) that were previously linked to AD. This study identified several significant gene- and pathway-level rare eQTLs, which further confirmed the importance of the immune system and inflammation in AD and highlighted the advantages of using a set-based eQTL approach for evaluating the effect of low-frequency and rare variants on gene expression. Full article

Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy. Full article