Exhaustive screens for disease susceptibility loci incorporating statistical interaction of genotypes: a comparison of likelihood-ratio-based and Akaike and Bayesian information criteria-based methods

Several recent papers have suggested that two-locus tests of association that incorporate gene × gene interaction can be more powerful than marginal, single-locus tests across a broad range of multilocus interaction models, even after conservative correction for multiple testing. However, because these two-locus tests are sensitive to marginal associations with either marker, they can be difficult to interpret, and it is not immediately clear how to use them to select a list of the most promising markers worthy of further study. Here we apply single- and two-locus tests to 29 single-nucleotide polymorphisms (SNPs) selected from the dense marker map in the simulated Genetic Analysis Workshop 15 data spanning several candidate regions (the HLA region, the four SNPs flanking "Locus D," and two regions on the q-arm of chromosome 6). We compare the proposed two-locus likelihood ratio tests (LRT) to Akaike and Bayesian Information Criteria (AIC and BIC) for model selection, as well as AIC- and BIC-weighted measures of "SNP importance." The latter provide summary measures of evidence for association between each SNP and disease – including potential interactions with one or more other SNPs – by summing over all one- and two-SNP models. Our results suggest that the LRT using conservative p-value criteria were sensitive (but not specific) in identifying associated markers. Standard AIC and BIC criteria were similarly sensitive but not specific. On the other hand, the AIC- and BIC-weighted importance measures yielded a specific but not very sensitive rule for SNP selection. Algorithms incorporating gene × gene interaction to prioritize markers for follow-up will require further development

Probing Higgs CPCP properties at the CEPC

In the Circular Electron Positron Collider (CEPC), a measurement of the Higgs $CP$ mixing through $e^{+} e^{-} \rightarrow Z H \rightarrow \mu^{+} \mu^{-} H(\rightarrow b \bar{b} / c \bar{c} / g g)$ process is presented, with $5.6\ \mbox{ab}^{-1}$$e^{+} e^{-}$collision data at the center-of-mass energy of$240\ \mathrm{GeV}$. In this study, the$CP$-violating parameter$\hat{\alpha}_{A \tilde{Z}}$is constrained between the region of$ -8.27\times 10^{-2}$and$8.09 \times 10^{-2}$and$\hat{\alpha}_{Z \tilde{Z}}$between$-2.15 \times 10^{-2}$and$2.02 \times 10^{-2}$at$95\%$confidence level. This study demonstrates the great potential of probing Higgs$CP$ properties at the CEPC

Genome-Wide and Candidate Gene Association Study of Cigarette Smoking Behaviors

The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, ≤10 versus >10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10−7) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10−5 for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10−3), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4×10−5), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up

Genome-Wide and Candidate Gene Association Study of Cigarette Smoking Behaviors

The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, ≤10 versus >10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10−7) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10−5 for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10−3), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4×10−5), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Precision Higgs physics at the CEPC

The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics. The Higgs boson will be the subject of extensive studies of the ongoing LHC program. At the same time, lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC, with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson. The Circular Electron Positron Collider~(CEPC) is one of such proposed Higgs factories. The CEPC is an $e^+e^-$ circular collider proposed by and to be hosted in China. Located in a tunnel of approximately 100~km in circumference, it will operate at a center-of-mass energy of 240~GeV as the Higgs factory. In this paper, we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.Comment: 46 pages, 37 figure