Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.

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 x 10(-3) and 4.37 x 10(-3), respectively, in the Chinese cohort and combined p values (obtained by Fisher's method) of 5.19 x 10(-5) and 1.02 x 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.

Genome-wide association study identifies two novel loci containing FLNB and SBF2 genes underlying stature variation.

Human stature, as an important physical index in clinical practice and a usual covariate in gene mapping of complex disorders, is a highly heritable complex trait. To identify specific genes underlying stature, a genome-wide association study was performed in 1000 unrelated homogeneous Caucasian subjects using Affymetrix 500K arrays. A group of seven contiguous markers in the region of SBF2 gene (Set-binding factor 2) are associated with stature, significantly so at the genome-wide level after false discovery rate (FDR) correction (FDR q = 0.034-0.042). Three SNPs in another SNP group in the Filamin B (FLNB) gene were also associated with stature, significantly so with FDR q = 0.042-0.048. In follow-up independent replication studies, rs10734652 in the SBF2 gene was significantly (P = 0.036) and suggestively (P = 0.07) associated with stature in Caucasian families and 1306 unrelated Caucasian subjects, respectively, and rs9834312 in the FLNB gene was also associated with stature in such two independent Caucasian populations (P = 0.008 in unrelated sample and P = 0.049 in family sample). Particularly, additional significant replication association signals were detected in Chinese, an ethnic population different from Caucasian, between rs9834312 and stature in 619 unrelated northern Chinese subjects (P = 0.017), as well as between rs10734652 and stature in 2953 unrelated southern Chinese subjects (P = 0.048). This study also provides additional replication evidence for some of the already published stature loci. These results, together with the known functional relevance of the SBF2 and FLNB genes to skeletal linear growth and bone formation, support that two regions containing FLNB and SBF2 genes are two novel loci underlying stature variation.

Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis.

Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 x 10(-4), Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 x 10(-4) -0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.

Genome-wide association scans identified CTNNBL1 as a novel gene for obesity.

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.

Surgical, Economic, and Psychological Impacts of SARS-COV-2 on a Kansas Community Hospital System.

The chief of surgery of a 264-bed acute care facility and clinic system in Topeka, KS, USA, gives a chronology that illustrates the rapid and profound clinical, economic, and emotional impact of the SARS-CoV-2 outbreak on his hospital and community. In his view, the pandemic has laid bare the weaknesses of several factors basic to the modern US health care system and the resulting economic crisis: just-in-time supply chain technology; foreign sourcing of masks, gowns, and critical equipment, all at critical shortages during the crisis; rural hospital closings; lack of excess capacity through maximization of utilization for efficiency; and an overreliance on high revenue elective procedures and tests. His team was tested by an emergency operation for bowel obstruction that put all the isolation protocols into action. Despite their readiness and the success of the operation and the potential for telemedicine as an alternative to in-person evaluations and outpatient visits, the forced cancellation of all elective operations have led to the loss of revenue for both hospital system and providers, furlough and termination of workers, and financial hardship and uncertainty.

Bivariate genome linkage analysis suggests pleiotropic effects on chromosomes 20p and 3p for body fat mass and lean mass.

Total body fat mass (TBFM) and total body lean mass (TBLM) are the major components of the human body. Although these highly correlated phenotypic traits are frequently used to characterize obesity, the specific shared genetic factors that influence both traits remain largely unknown. Our study was aimed at identifying common quantitative trait loci (QTLs) contributing to both TBFM and TBLM. We performed a whole genome-linkage scan study in a large sample of 3255 subjects from 420 Caucasian pedigrees. Bivariate linkage analysis was carried out in both the entire sample and gender-specific subsamples. Several potentially important genomic regions that may harbour QTLs important for TBFM and TBLM were identified. For example, 20p12-11 achieved a LOD score of 2.04 in the entire sample and, in the male subsample, two genomic regions, 20p12 (LOD=2.08) and 3p26-25 (LOD=1.92), showed suggestive linkage. In addition, two-point linkage analyses for chromosome X showed suggestive linkages on Xp22 in the entire sample (LOD=2.14) and significant linkage on Xp22 in the female subsample (LOD=3.05). Complete pleiotropy was suggested for 20p12 and 3p26-25 in males. Our results suggest that QTLs on chromosomes 20p12, 3p26-25 and Xp22 may jointly influence TBFM and TBLM. Further fine mapping and gene identification studies for these pleiotropic effects are needed.

Chromosome 2q32 may harbor a QTL affecting BMD variation at different skeletal sites.

UNLABELLED: BMDs at different skeletal sites share some common genetic determinants. Using PCA and bivariate linkage analysis, we identified a QTL on chromosome 2q32 with significant pleiotropic effects on BMDs at different skeletal sites. INTRODUCTION: BMDs at the hip, spine, and forearm are genetically correlated, suggesting the existence of quantitative trait loci (QTLs) with concurrent effects on BMDs at these three skeletal sites. Consequently, it is important to identify these QTLs in the human genome and, for those implicated QTLs, it is important to differentiate between pleiotropic effects, caused by a single gene that concurrently effects these traits, and co-incident linkage, caused by multiple, closely linked, genes that independently effect these traits. MATERIALS AND METHODS: For a sample of 451 American white pedigrees made up of 4,498 individuals, we evaluated the correlations between BMDs at the three skeletal sites. We carried out principal component analysis (PCA) for the three correlated traits and obtained a major component, PC1, which accounts for >75% of the co-variation of BMDs at the three sites. We subsequently conducted a whole genome linkage scan for PC1 and performed bivariate linkage analysis for pairs of the three traits (i.e., forearm/spine BMD, hip/forearm BMD, and hip/spine BMD). RESULTS: Chromosome region 2q32, near the marker GATA65C03M, showed strong linkage to PC1 (LOD = 3.35). Subsequent bivariate linkage analysis substantiated linkage at 2q32 for each trait pair (LOD scores were 2.65, 2.42, and 2.13 for forearm/spine BMD, hip/forearm BMD, and hip/spine BMD, respectively). Further analyses rejected the hypothesis of co-incident linkage (p(0)[forearm/spine] = 0.0005, p(0)[hip/forearm] = 0.004, p(0)(hip/spine] = 0.001) but failed to reject the hypothesis of pleiotropy (p(1)[forearm/spine] = 0.35, p(1)[hip/forearm] = 0.07, p(1)[hip/spine] = 0.15). CONCLUSIONS: Our results strongly support the conclusion that chromosome region 2q32 may harbor a QTL with pleiotropic effects on BMDs at different skeletal sites.

Managing the academic orthopaedic practice as a business.

Efforts by academic orthopaedic surgeons to provide patient care, educate trainees, and perform research into the various facets of musculoskeletal afflictions are being challenged by changes in technology, financing, and demographics. In the current economy, efficient, cost-effective management is essential for survival of an academic or private orthopaedic practice. All practitioners should be acutely aware of the principles involved in the management of a private practice, but academic practices must also deal with such factors as the teaching of residents and medical students, the expectation of comprehensive coverage, indigent case load, and research. Orthopaedic surgeons in the academic environment must proactively manage their practices as businesses to maintain sufficient financial viability to support the other endeavors. Academicians therefore must have an understanding of the principles that will impact their practice and assist in the analysis of an academic practice's productivity.

Whole genome distribution and ethnic differentiation of copy number variation in Caucasian and Asian populations.

Although copy number variation (CNV) has recently received much attention as a form of structure variation within the human genome, knowledge is still inadequate on fundamental CNV characteristics such as occurrence rate, genomic distribution and ethnic differentiation. In the present study, we used the Affymetrix GeneChip(R) Mapping 500K Array to discover and characterize CNVs in the human genome and to study ethnic differences of CNVs between Caucasians and Asians. Three thousand and nineteen CNVs, including 2381 CNVs in autosomes and 638 CNVs in X chromosome, from 985 Caucasian and 692 Asian individuals were identified, with a mean length of 296 kb. Among these CNVs, 190 had frequencies greater than 1% in at least one ethnic group, and 109 showed significant ethnic differences in frequencies (p<0.01). After merging overlapping CNVs, 1135 copy number variation regions (CNVRs), covering approximately 439 Mb (14.3%) of the human genome, were obtained. Our findings of ethnic differentiation of CNVs, along with the newly constructed CNV genomic map, extend our knowledge on the structural variation in the human genome and may furnish a basis for understanding the genomic differentiation of complex traits across ethnic groups.

Genome-wide association study of exercise behavior in Dutch and American adults.

INTRODUCTION: The objective of this study was to identify genetic variants that are associated with adult leisure time exercise behavior using genome-wide association (GWA) in two independent samples. METHODS: Exercise behavior was measured in 1644 unrelated Dutch and 978 unrelated American adults of European ancestry with detailed questions about type, frequency, and duration of exercise. Individuals were classified into regular exercisers or nonexercisers using a threshold of 4 MET·h (metabolic equivalents-hours per week). GWA analyses of ∼1.6 million observed and imputed Single Nucleotide Polymorphism (SNP) were conducted in both samples independently using logistic regression in SNPTEST, including sex, age, and body mass index as covariates. A meta-analysis of the results was performed using the weighted inverse variance method in METAL. RESULTS: Thirty-seven novel SNPs in the PAPSS2 gene and in two intergenic regions on chromosomes 2q33.1 and 18p11.32 were associated with exercise participation (pooled P values <1.0 × 10(-5)). Previously reported associations (ACE, CASR, CYP19A1, DRD2, LEPR, and MC4R genes) or linkage findings (2p22.3, 4q28, 4q31.21 7p13, 9q31, 11p15, 13q22, 15q13, 18q12.2, 18q21.1, 19p13.3, and 20q12) were not replicated, although suggestive evidence was found for association to rs12405556 in the LEPR gene (pooled P value 9.7 × 10(-4); American sample, P value 9.8 × 10(-5)) and for association to rs8036270 in the GABRG3 gene (pooled P value 4.6 × 10(-5)) in the linkage region 15q12-13. CONCLUSIONS: The heritability of leisure time exercise behavior is likely to be accounted for by many genetic variants with small effect size. These can be detected by GWA as was shown here for the PAPSS2 gene, but larger samples with genome-wide genotypes and high-quality exercise data are needed for further progress.

A bivariate whole genome linkage study identified genomic regions influencing both BMD and bone structure.

Areal BMD (aBMD) and areal bone size (ABS) are biologically correlated traits and are each important determinants of bone strength and risk of fractures. Studies showed that aBMD and ABS are genetically correlated, indicating that they may share some common genetic factors, which, however, are largely unknown. To study the genetic factors influencing both aBMD and ABS, bivariate whole genome linkage analyses were conducted for aBMD-ABS at the femoral neck (FN), lumbar spine (LS), and ultradistal (UD)-forearm in a large sample of 451 white pedigrees made up of 4498 individuals. We detected significant linkage on chromosome Xq27 (LOD = 4.89) for LS aBMD-ABS. In addition, we detected suggestive linkages at 20q11 (LOD = 3.65) and Xp11 (LOD = 2.96) for FN aBMD-ABS; at 12p11 (LOD = 3.39) and 17q21 (LOD = 2.94) for LS aBMD-ABS; and at 5q23 (LOD = 3.54), 7p15 (LOD = 3.45), Xq27 (LOD = 2.93), and 12p11 (LOD = 2.92) for UD-forearm aBMD-ABS. Subsequent discrimination analyses indicated that quantitative trait loci (QTLs) at 12p11 and 17q21 may have pleiotropic effects on aBMD and ABS. This study identified several genomic regions that may contain QTLs important for both aBMD and ABS. Further endeavors are necessary to follow these regions to eventually pinpoint the genetic variants affecting bone strength and risk of fractures.

Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study.

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 approximately 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 3.72x10(-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 8.62x10(-3) and 2.44x10(-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 approximately 0.6 kb apart from the most significant SNP detected in our GWAS (rs7595412), achieved a p value of 7.66x10(-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.