WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ~2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10-9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10-12, and -0.16 SD per G allele, P = 1.2×10-15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10-6 and rs2707466: OR = 1.22, P = 7.2×10-6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16-/- mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10-13<P<5.9×10-4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture. © 2012 Zheng et al.

The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; And causes varying phenotypic severity of osteogenesis imperfecta type V

Background The genetic mutation resulting in osteogenesis imperfecta (OI) type V was recently characterised as a single point mutation (c.-14C > T) in the 5' untranslated region (UTR) of IFITM5, a gene encoding a transmembrane protein with expression restricted to skeletal tissue. This mutation creates an alternative start codon and has been shown in a eukaryotic cell line to result in a longer variant of IFITM5, but its expression has not previously been demonstrated in bone from a patient with OI type V. Methods Sanger sequencing of the IFITM5 5' UTR was performed in our cohort of subjects with a clinical diagnosis of OI type V. Clinical data was collated from referring clinicians. RNA was extracted from a bone sample from one patient and Sanger sequenced to determine expression of wild-type and mutant IFITM5. Results: All nine subjects with OI type V were heterozygous for the c.-14C > T IFITM5 mutation. Clinically, there was heterogeneity in phenotype, particularly in the manifestation of bone fragility amongst subjects. Both wild-type and mutant IFITM5 mRNA transcripts were present in bone. Conclusions The c.-14C > T IFITM5 mutation does not result in an RNA-null allele but is expressed in bone. Individuals with identical mutations in IFITM5 have highly variable phenotypic expression, even within the same family.

Genetic studies in osteoporosis: The end of the beginning

Osteoporosis and disorders of bone fragility are highly heritable, but despite much effort the identities of few of the genes involved has been established. Recent developments in genetics such as genome-wide association studies are revolutionizing research in this field, and it is likely that further contributions will be made through application of next-generation sequencing technologies, analysis of copy number variation polymorphisms, and high-throughput mouse mutagenesis programs. This article outlines what we know about osteoporosis genetics to date and the probable future directions of research in this field.

Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus

Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fractures applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5×10-8. In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p=4.6×10-8. However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% CI: 0.98-1.14; p=0.17), displaying high degree of heterogeneity (I2=57%; Qhet p=0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p=0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures.

Genetic determinants of bone density and fracture risk: State of the art and future directions

Context: Osteoporosis is a common, highly heritable condition that causes substantial morbidity and mortality, the etiopathogenesis of which is poorly understood. Genetic studies are making increasingly rapid progress in identifying the genes involved. Evidence Acquisition and Synthesis: In this review, we will summarize the current understanding of the genetics of osteoporosis based on publications from PubMed from the year 1987 onward. Conclusions: Most genes involved in osteoporosis identified to date encode components of known pathways involved in bone synthesis or resorption, but as the field progresses, new pathways are being identified. Only a small proportion of the total genetic variation involved in osteoporosis has been identified, and new approaches will be required to identify most of the remaining genes.

ESR evidence for 2 coexisting liquid phases in deeply supercooled bulk water

Using electron spin resonance spectroscopy (ESR), we measure the rotational mobility of probe molecules highly diluted in deeply supercooled bulk water and negligibly constrained by the possible ice fraction. The mobility increases above the putative glass transition temperature of water, T-g = 136 K, and smoothly connects to the thermodynamically stable region by traversing the so called "no man's land" (the range 150-235 K), where it is believed that the homogeneous nucleation of ice suppresses the liquid water. Two coexisting fractions of the probe molecules are evidenced. The 2 fractions exhibit different mobility and fragility; the slower one is thermally activated (low fragility) and is larger at low temperatures below a fragile-to-strong dynamic cross-over at approximate to 225 K. The reorientation of the probe molecules decouples from the viscosity below approximate to 225 K. The translational diffusion of water exhibits a corresponding decoupling at the same temperature [Chen S-H, et al. (2006) The violation of the Stokes-Einstein relation in supercooled water. Proc Natl Acad Sci USA 103:12974-12978]. The present findings are consistent with key issues concerning both the statics and the dynamics of supercooled water, namely the large structural fluctuations [Poole PH, Sciortino F, Essmann U, Stanley HE (1992) Phase behavior of metastable water. Nature 360: 324-328] and the fragile-to-strong dynamic cross-over at approximate to 228 K [Ito K, Moynihan CT, Angell CA (1999) Thermodynamic determination of fragility in liquids and a fragile-tostrong liquid transition in water. Nature 398: 492-494].

Combined Jewish Philanthropies (Boston, Mass.) records, undated, 1865-1989 (bulk 1942-1979)

The Combined Jewish Philanthropies (CJP) of Boston, Massachusetts is the oldest federated Jewish philanthropy in the United States. The current incarnation of CJP was formed in 1960, when two separate federated philanthropies – the Combined Jewish Appeal and Associated Jewish Philanthropies – merged to create a single organization dedicated to serving the needs of Boston’s Jewish community. CJP’s records contain the history of several other organizations, from the forerunners of the current Federation to the Jewish institutions supported by CJP. Their beginnings can be traced to the founding of the United Hebrew Benevolent Association (UHBA) in 1864 at the Pleasant Street Synagogue (now Temple Israel.) This collection contains meeting minutes, correspondence, photographs, scrapbooks, financial documents and ledgers, appeal information, publicity, programs, brochures and other written documents relating CJP’s history.

Ernest W. Michel Papers, 1698, 1938-1996 (bulk 1946-1987)

This collection contains the papers of Ernest W. Michel, Holocaust Survivor Journalist and public speaker,including clippings of newspaper articles written by and about Michel, correspondence between Michel and many important Jewish and political figures and autograph files, which Michel collected. Many of these files concern Michel’s Holocaust experiences, speaking engagements, the World Gathering of Jewish Holocaust Survivors, and Michel’s work with the United Jewish Appeal.

Schoolman family papers, undated, 1889-1994

The Schoolman Papers reflect Dr. Albert P. and Mrs. Bertha Schoolmans' staunch dedication to Jewish education, Jewish causes, and Israel. Bertha Schoolman, a lifelong member of Hadassah, assisted thousands of Israeli youth as chairman of the Youth Aliyah Committee. Her diaries, photos, scrapbooks, and correspondence record her numerous visits to Israel on which she helped set up schools, met with Israeli dignitaries, and participated in Zionist Conferences and events. The collection includes a 1936 letter from Hadassah founder, Henrietta Szold, praising Mrs. Schoolman's work as well as a letter from the father of Anne Frank, thanking Mrs. Schoolman for naming a Youth Aliyah center the "Anne Frank Haven" after his later daughter.

North American Jewish Students Appeal records, undated, 1962, 1964-1996 (bulk 1971-1995)

The records of the North American Jewish Students Appeal (NAJSA or APPEAL) contains documents on two levels of concern: those documents dealing with the NAJSA as a student-run organization promoting Jewish identity among college-aged youth; and those documents dealing with the APPEAL as a fundraising organization for several well-known student constituent organizations. The Constituents were: the Jewish Student Press Service, Lights in Action, the North American Jewish Students Network, the Progressive Zionist Caucus, Response: A Contemporary Jewish Review, Yavneh Religious Students Organization, and Yugntruf Youth for Yiddish. Documents include correspondence, financial records, minutes, press releases, information on grants awarded to student organizations for programming and publishing, student journals, and newspapers, photographs, and ephemera.

Temple Emanuel (Andover, Mass.) records, 1939-2001; and Part II (addendum), undated 1952-2004

Temple Emanuel was founded in 1920 in Lawrence, Massachusetts. It began by serving a small immigrant Jewish community that has since grown to an affluent and lively congregation of about 600 families. This growth occurred largely under the tenure of Rabbi Harry A. Roth, who lead the congregation from 1962 until 1990 and oversaw the temple’s move to Andover, Massachusetts. This collection includes correspondence, photographs, and sermons.

Grand Street Boys' Association (New York, N.Y.) Records, undated, 1907-1968, bulk 1940-2000.

The Grand Street Boys' Association began in 1916 as a reunion of men who had grown up on or near Grand Street in the Lower East Side neighborhood of Manhattan and quickly grew into an active club, open to all men (and eventually women) regardless of religion, ethnicity, or social class. The Association promoted welfare projects, acts of fellowship and tolerance, scholarships, youth employment, war efforts, and the elimination of discrimination in sports, among other projects. The collection documents the activities of the Association, as well as the Grand Street Boys' Foundation, its financial arm established in 1945, and its Hobbycraft Program, a charitable program tasked with collecting and redistributing donated items to charitable and nonprofit organizations. Materials include administrative records, financial records, correspondence, minutes, membership records, newsletters, yearbooks, artifacts, speeches, and photographs relating to both the New York Grand Street Boys' Association and the Association's Grand Street House in England. Series I, comprising the majority of the collection, contains the records of the Grand Street Boys' Association. In it are extensive membership records, meeting minutes, annual yearbooks, financial records, administrative material, newsletters, and artifacts. Series II documents the Grand Street Boys' Foundation and contains administrative records and financial records. Some overlap of material will be found in Series I and II such as material pertaining to the relationship between the Association and Foundation. Series III consists of photographs documenting both the Association and Foundation. The photographs show members and highlight the activities of the Grand Street Boys.

American Jewish Committee. Office of Jewish War Records, undated, 1918-1921, 1962.

The records consist of documentation of the American Jewish Committee's project to describe Jewish participation in the United States Armed Forces during World War I. The bulk of the material consists of questionnaires that the AJC sent to servicemen to determine Jewish identity, which contain information on personal identification and details of military service. Responses to the questionnaire come from both Jews and non-Jews. In addition, the collection contains office papers concerning the project and a ledger of manuscripts. The manuscripts document the distribution of records the Office of Jewish War Records collected, as well as list Jews who died or were given military honors.

Rabb Family/Stop & Shop collection, 1912-1989.

The Rabinovitz/Rabb family arrived in Boston from Russia in the 1890s. Around 1914 they founded Economy Grocery Stores, which became Stop & Shop in 1946. In addition to building their grocery company into a successful business, the family is known for its philanthropy and active involvement in the Jewish community. The collection contains materials relating to the Rabb family and to the business operations of Stop & Shop until 1989. The materials in this collection include historical sketches, newspaper clippings, press releases, correspondence, memoranda, minutes, reports, advertisements, certificates, speeches, interviews, films, and photographs.

Congregation Beth Israel Hartford Connecticut collection, 1920-1999

Congregation Beth Israel was founded in 1843 and is Connecticut's oldest synagogue. Originally established as an Orthodox congregation, the synagogue eventually converted to Reform and was one of the founding members of the Union of American Hebrew Congregations (Union for Reform Judaism) in 1877. This collection includes event flyers, programs for services, sermons, anniversary books with historical information, and bulletins. Box 1: General/Miscellaneous Materials 1927-1970. 100th Anniversary /Programs and Invitations 1943. 125th Anniversary/Program 1968. Publications/Bulletins 1920-1959. Box 2: Publications/ Bulletings 1950-1969. Box 3: Publications/ Bulletins 1960-1989. Box 4: Publications/ Bulletin 1989-1999.