Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies

Genome-wide association is a promising approach to identify common genetic variants that predispose to human disease. Because of the high cost of genotyping hundreds of thousands of markers on thousands of subjects, genome-wide association studies often follow a staged design in which a proportion (pi(samples)) of the available samples are genotyped on a large number of markers in stage 1, and a proportion (pi(samples)) of these markers are later followed up by genotyping them on the remaining samples in stage 2. The standard strategy for analyzing such two-stage data is to view stage 2 as a replication study and focus on findings that reach statistical significance when stage 2 data are considered alone. We demonstrate that the alternative strategy of jointly analyzing the data from both stages almost always results in increased power to detect genetic association, despite the need to use more stringent significance levels, even when effect sizes differ between the two stages. We recommend joint analysis for all two-stage genome-wide association studies, especially when a relatively large proportion of the samples are genotyped in stage 1 (pi(samples) >or= 0.30), and a relatively large proportion of markers are selected for follow-up in stage 2 (pi(markers) >or= 0.01).     

Un nouveau type de détermination chromosomique du sexe chez les mammifèresEllobius lutescens Th. etMicrotus (Chilotus) oregoni Bachm. (Muridés-Microtinés)

Summary (1)Ellobius lutescens andMicrotus oregoni show the same type of sex-chromosomes. The diploid number is odd in both sexes, seventeen.(2) The odd element ofEllobius is morphologically alike in the male and in the female. InM. oregoni, the odd element of the male is acrocentric, that of the female metacentric.(3) Following a hypothesis ofWhite, it seems very probable that the heterochromosome of the male is built of the primitiveY (short arm) and the primitiveX (long arm) linked together. In the female of the same species (M. oregoni), the sex-chromosome represents both theX fused together.(4) Only the half of the Zygotes may develope, the other half being lethal.(5) The close kinship betweenEllobius andM. oregoni is certain, a parallel evolution appearing as highly improbable.     

Mutations in KERA, encoding keratocan, cause cornea plana

Specialized collagens and small leucine-rich proteoglycans (SLRPs) interact to produce the transparent corneal structure. In cornea plana, the forward convex curvature is flattened, leading to a decrease in refraction. A more severe, recessively inherited form (CNA2; MIM 217300) and a milder, dominantly inherited form (CNA1; MIM 121400) exist. CNA2 is a rare disorder with a worldwide distribution, but a high prevalence in the Finnish population. The gene mutated in CNA2 was assigned by linkage analysis to 12q (refs 4, 5), where there is a cluster of several SLRP genes. We cloned two additional SLRP genes highly expressed in cornea: KERA (encoding keratocan) in 12q and OGN (encoding osteoglycin) in 9q. Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein. Our data establish that mutations in KERA cause CNA2. CNA1 patients had no mutations in these proteoglycan genes.     

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.     

Antineoplastic agents 32. The pseudoguaianolide helenalin

Zusammenfassung Aus der PflanzeHelenium autummnale (Familie compositae) wurde ein alkolischer Extrakt gewonnen, der cytotoxische und antileukämische Aktivität zeigte und die Helenalin (I) als wirksame Komponente enthielt. Die Behandlung von Mäusen, die Träger von P 388 lymphocytischer Leukämie waren, ergab eine beachtliche (T/C 220) Verlängerung ihrer Lebenserwartung. Die Substanz zeigte ausserdem einen wachstumshemmenden Einfluss auf das Walker 256 Karzinom. Helenalin ist das erste Sesquiterpen vom Pseudoguaianolid Typ, welches in vivo eine solche antineoplastische Aktivität zeigt.

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For part 31, refer toG. R. Pettit, P. Traxler andC. P. Pase, Lloydia36, in press (1973).

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This investigation was supported by Public Health Service Research Grants No. CA-10612-01 to No. CA-10612-04 from the National Cancer Institute and was performed pursuant to contract No. NCI-C-71-2308 with the Division of Cancer Treatment, National Cancer Institute, Department of Health, Education and Welfare. A grant from the C.S.I.R. (South Africa) to G.M.C. is also gratefully acknowledged. In addition, we are indebted to Dr.L. Johnston for identifying theHelenium autumnale, toBetty J. Abbot and her colleagues at the National Cancer Institute, for the biological studies, and toJ. F. Day for assisting with both the laboratory scale and preparative scale plant extraction procedures.     

Effect of cortisone or triiodothyronine administration to pregnant rats on lysosomal hydrolases in fetal forebrain and cerebellum

Triiodothyronine injected daily to pregnant rats for the last week of gestation (50 microgram/100 g b.wt) increased the specific activities of 5 acid glycosidases in the fetal forebrain and cerebellum. Cortisone (50 mg/100 g b.wt) administered in the same period had no effect on cerebellum acid hydrolases, but decreased their activity in the forebrain.     

Applications of a generalized data-management language in medicine: Some recent experience at Stanford university

Zusammenfassung Um den Zugang zum Computer auch für den Nichtfachmann möglichst einfach und effektiv zu gestalten, müssen neue Programmiertechniken entwickelt werden. Ein Teil dieser Neuentwicklungen beschäftigt sich mit dem Aufbau und dem Gebrauch von Computer-Dateien. Zu diesem Zwecke wurde DIRAC an der Stanford-University entwickelt und getestet. Diese Sprache ist die erste einer ganzen Familie von Prototypen, welche eingesetzt werden, um die organisatorischen Probleme der Speicherung und Wiederauffindung wissenschaftlicher Information zu lösen. Die Sprache ist so konstruiert, dass die Benützer via einen Fernschreiber, der weit von der Computer-Zentrale entfernt aufgestellt sein kann, mit Hilfe einfacher Schlüsselwörter ihren Zwecken angepasste Kartotheken aufbauen können («create»), die einmal gespeicherte Information ergänzen, zerstören oder modifizieren können («up date»), die Kartothek nach fast beliebigen Kriterien abfragen und gesuchte Informationen heraussortieren können («query») sowie den Inhalt der ganzen Kartothek herausdrucken und einfach statistisch bearbeiten lassen können («status»). Ein kurzer Überblick über den Sprachaufbau von DIRAC und Beispiele für den Gebrauch von DIRAC durch verschiedene medizinische Abteilungen der Stanford-University sind beschrieben.