Obesity is a major public health problem with strong genetic determination; however, the genetic factors underlying obesity are largely unknown. In this study, we performed a genome-wide association scan for obesity by examining approximately 500 000 single-nucleotide polymorphisms (SNPs) in a sample of 1000 unrelated US Caucasians. We identified a novel gene, CTNNBL1, which has multiple SNPs associated with body mass index (BMI) and fat mass. The most significant SNP, rs6013029, achieved experiment-wise P-values of 2.69 x 10(-7) for BMI and of 4.99 x 10(-8) for fat mass, respectively. The SNP rs6013029 minor allele T confers an average increase in BMI and fat mass of 2.67 kg/m(2) and 5.96 kg, respectively, compared with the alternative allele G. We further genotyped the five most significant CTNNBL1 SNPs in a French case-control sample comprising 896 class III obese adults (BMI > or = 40 kg/m(2)) and 2916 lean adults (BMI < 25 kg/m(2)). All five SNPs showed consistent associations with obesity (8.83 x 10(-3) < P < 6.96 x 10(-4)). Those subjects who were homozygous for the rs6013029 T allele had 1.42-fold increased odds of obesity compared with those without the T allele. The protein structure of CTNNBL1 is homologous to beta-catenin, a family of proteins containing armadillo repeats, suggesting similar biological functions. beta-Catenin is involved in the Wnt/beta-catenin-signaling pathway which appears to contribute to maintaining the undifferentiated state of pre-adipocytes by inhibiting adipogenic gene expression. Our study hence suggests a novel mechanism for the development of obesity, where CTNNBL1 may play an important role. Our study also provided supportive evidence for previously identified associations between obesity and INSIG2 and PFKP, but not FTO.

Introduction The objective of this study was to identify genetic variants that are associated with adult leisure-time exercise behavior using genome-wide association in two independent samples. Methods Exercise behavior was measured in 1,772 unrelated Dutch and 978 unrelated American adults with detailed questions about type, frequency and duration of exercise. Individuals were classified into regular exercisers or non-exercisers using a threshold of 4 METhours (metabolic equivalents*hours per week). Regular exercisers were further divided into 5 categories of METhours, ranging from moderate (>=4 METhours) to highly vigorous (>=40 METhours) exercisers. Genome-wide association analyses with a total of 470,719 SNPs were conducted in both samples independently using regression-based techniques in SNPtest, including sex, age and BMI as covariates. Results SNPs located in SGIP1, DNASE2B, PRSS16, ERCC2 and PAPSS2 were associated with exercise participation (combined p-value between 0.0004 and 4.5*10-6 with the same direction of allelic effects in both samples). Associations of candidate genes based on existing literature were replicated for the LEPR gene in the American sample (rs12405556, p=0.0005) and for the CYP19A1 gene in the Dutch sample (rs2470158, 0.0098). Conclusion Two genes (SGIP1 and LEPR) are expressed in the hypothalamus and involved in the regulation of energy homeostasis. Their effects were independent of BMI, suggesting a direct role of hypothalamic factors in the drive to exercise.

Low lean body mass (LBM) is related to a series of health problems, such as osteoporotic fracture and sarcopenia. Here we report a genome-wide association (GWA) study on LBM variation, by using Affymetrix 500K single-nucleotide polymorphism (SNP) arrays. In the GWA scan, we tested 379,319 eligible SNPs in 1,000 unrelated US whites and found that two SNPs, rs16892496 (p = 7.55 x 10(-8)) and rs7832552 (p = 7.58 x 10(-8)), within the thyrotropin-releasing hormone receptor (TRHR) gene were significantly associated with LBM. Subjects carrying unfavorable genotypes at rs16892496 and rs7832552 had, on average, 2.70 and 2.55 kg lower LBM, respectively, compared to those with alternative genotypes. We replicated the significant associations in three independent samples: (1) 1488 unrelated US whites, (2) 2955 Chinese unrelated subjects, and (3) 593 nuclear families comprising 1972 US whites. Meta-analyses of the GWA scan and the replication studies yielded p values of 5.53 x 10(-9) for rs16892496 and 3.88 x 10(-10) for rs7832552. In addition, we found significant interactions between rs16892496 and polymorphisms of several other genes involved in the hypothalamic-pituitary-thyroid and the growth hormone-insulin-like growth factor-I axes. Results of this study, together with the functional relevance of TRHR in muscle metabolism, support the TRHR gene as an important gene for LBM variation.

For females, menarche is a most significant physiological event. Age at menarche (AAM) is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS) examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects—all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan), which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR) q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09×10−3 and 4.37×10−3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19×10−5 and 1.02×10−4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2), a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

Osteoporosis, the most prevalent metabolic bone disease among older people, increases risk for low trauma hip fractures (HF) that are associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of the key measurable risk factors for HF. Although hip BS is highly genetically determined, genetic factors underlying the trait are still poorly defined. Here, we performed the first genome-wide association study (GWAS) of hip BS interrogating ∼380,000 SNPs on the Affymetrix platform in 1,000 homogeneous unrelated Caucasian subjects, including 501 females and 499 males. We identified a gene, PLCL1 (phospholipase c-like 1), that had four SNPs associated with hip BS at, or approaching, a genome-wide significance level in our female subjects; the most significant SNP, rs7595412, achieved a p value of 3.72×10−7. The gene's importance to hip BS was replicated using the Illumina genotyping platform in an independent UK cohort containing 1,216 Caucasian females. Two SNPs of the PLCL1 gene, rs892515 and rs9789480, surrounded by the four SNPs identified in our GWAS, achieved p values of 8.62×10−3 and 2.44×10−3, respectively, for association with hip BS. Imputation analyses on our GWAS and the UK samples further confirmed the replication signals; eight SNPs of the gene achieved combined imputed p values<10−5 in the two samples. The PLCL1 gene's relevance to HF was also observed in a Chinese sample containing 403 females, including 266 with HF and 177 control subjects. A SNP of the PLCL1 gene, rs3771362 that is only ∼0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66×10−3 (odds ratio = 0.26) for association with HF. Additional biological support for the role of PLCL1 in BS comes from previous demonstrations that the PLCL1 protein inhibits IP3 (inositol 1,4,5-trisphosphate)-mediated calcium signaling, an important pathway regulating mechanical sensing of bone cells. Our findings suggest that PLCL1 is a novel gene associated with variation in hip BS, and provide new insights into the pathogenesis of HF.

Let $G=(V(G),E(G))$ be a graph with vertex set $V(G)$ and edge set $E(G)$. The subdivision graph $\mathcal{S}(G)$ of a graph $G$ is the graph obtained by inserting a new vertex into every edge of $G$. Let $G_1$ and $G_2$ be two vertex disjoint graphs. The subdivision-vertex neighbourhood corona of $G_1$ and $G_2$, denoted by $G_1 \boxdot G_2$, is the graph obtained from $\mathcal{S}(G_1)$ and $|V(G_1)|$ copies of $G_2$, all vertex disjoint, and joining the neighbours of the $i$th vertex of $V(G_1)$ to every vertex in the $i$th copy of $G_2$. The subdivision-edge neighbourhood corona of $G_1$ and $G_2$, denoted by $G_1 \boxminus G_2$, is the graph obtained from $\mathcal{S}(G_1)$ and $|I(G_1)|$ copies of $G_2$, all vertex disjoint, and joining the neighbours of the $i$th vertex of $I(G_1)$ to every vertex in the $i$th copy of $G_2$, where $I(G_1)$ is the set of inserted vertices of $\mathcal{S}(G_1)$. In this paper we determine the adjacency spectra, the Laplacian spectra and the signless Laplacian spectra of $G_1\boxdot G_2$ (respectively, $G_1\boxminus G_2$) in terms of the corresponding spectra of $G_1$ and $G_2$. As applications, these results enable us to construct infinitely many pairs of cospectral graphs, and using the results on the Laplacian spectra of subdivision-vertex neighbourhood coronae, new families of expander graphs are constructed from known ones.Comment: arXiv admin note: substantial text overlap with arXiv:1209.5906, arXiv:1212.061

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Femoral neck compression strength index (fCSI), a novel phenotypic parameter that integrates bone density, bone size, and body size, has significant potential to improve hip fracture risk assessment. The genetic factors underlying variations in fCSI, however, remain largely unknown. Given the important roles of the receptor activator of the nuclear factor-κB ligand/receptor activator of the nuclear factor-κB/osteoprotegerin (RANKL/RANK/OPG) pathway in the regulation of bone remodeling, we tested the associations between RANKL/RANK/OPG polymorphisms and variations in fCSI as well as its components (femoral neck bone mineral density [fBMD], femoral neck width [FNW], and weight). This was accomplished with a sample comprising 1873 subjects from 405 Caucasian nuclear families. Of the 37 total SNPs studied in these three genes, 3 SNPs, namely, rs12585014, rs7988338, and rs2148073, of RANKL were significantly associated with fCSI (P = 0.0007, 0.0007, and 0.0005, respectively) after conservative Bonferroni correction. Moreover, the three SNPs were approximately in complete linkage disequilibrium. Haplotype-based association tests corroborated the single-SNP results since haplotype 1 of block 1 of the RANKL gene achieved an even more significant association with fCSI (P = 0.0003) than any of the individual SNPs. However, we did not detect any significant associations of these genes with fBMD, FNW, or weight. In summary, our findings suggest that the RANKL gene may play an important role in variation in fCSI, independent of fBMD and non-fBMD components. KeywordsFemoral neck compression strength index; Femoral neck bone mineral density; Femoral neck width; RANKL/RANK/OPG gene; Quantitative transmission disequilibrium test Osteoporosis is a systemic skeletal disorder characterized by impaired bone strength and an elevated risk of osteoporotic fractures. Osteoporosis represents a major health problem throughout the world and the most serious consequence of osteoporosis is hip fracture, which has a high associated morbidity and mortality [1]. Currently, measurements of bone mineral density (BMD) are widely used to assess hip fracture risk [2,3]. However, BMD alone can only account for about 50-70% of total bone strength variation [4]. Among other risk factors of hip fracture, femoral neck width (FNW) and body weight have been repeatedly reported to be correlated with hip fracture risk [5][6][7][8][9][10]. Femoral neck compression strength index (fCSI) [11], a function of femoral neck BMD (fBMD), FNW, and weight based on structural engineering principles, may have the potential to improve hip fracture risk assessment. Karlamangla et al. [11] observed that a 1-standard-deviation (SD) decrease in fCSI was associated with an approximately 2.56-fold increase in hip fracture risk (P < 0.0001), while a 1-SD decrease in fBMD was associated with only a 1.96-fold increase in hip fracture (P = 0.0013). [18][19][20]. In the current study, for the first time, we comparatively examined the influence of RANKL/RANK/OPG gene variant...