Portrait of Ralph and Joan Grahme with Ralph's sister Ilse Schuster nee Gottschalk and her husband James at restaurant "Old Vienna"; London, England.

Left to right: Ralph Grahme, Joan Grahme, Ilse Schuster nee Gottschalk, and James Schuster;

FTO genotype is associated with phenotypic variability of body mass index

There is evidence across several species for genetic control of phenotypic variation of complex traits1, 2, 3, 4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ~170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5, 6, 7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ~0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9, 10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

Portrait of Ralph and Joan Grahme with Ralph's sister Ilse Schuster nee Gottschalk and her husband James at restaurant "Old Vienna"; London, England.

Left to right: Ralph Grahme, Joan Grahme, Ilse Schuster nee Gottschalk, and James Schuster;

Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10−9 to P = 1.8 × 10−40) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10−3 to P = 1.2 × 10−13). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

The conservation status of the world’s reptiles

Effective and targeted conservation action requires detailed information about species, their distribution, systematics and ecology as well as the distribution of threat processes which affect them. Knowledge of reptilian diversity remains surprisingly disparate, and innovative means of gaining rapid insight into the status of reptiles are needed in order to highlight urgent conservation cases and inform environmental policy with appropriate biodiversity information in a timely manner. We present the first ever global analysis of extinction risk in reptiles, based on a random representative sample of 1500 species (16% of all currently known species). To our knowledge, our results provide the first analysis of the global conservation status and distribution patterns of reptiles and the threats affecting them, highlighting conservation priorities and knowledge gaps which need to be addressed urgently to ensure the continued survival of the world’s reptiles. Nearly one in five reptilian species are threatened with extinction, with another one in five species classed as Data Deficient. The proportion of threatened reptile species is highest in freshwater environments, tropical regions and on oceanic islands, while data deficiency was highest in tropical areas, such as Central Africa and Southeast Asia, and among fossorial reptiles. Our results emphasise the need for research attention to be focussed on tropical areas which are experiencing the most dramatic rates of habitat loss, on fossorial reptiles for which there is a chronic lack of data, and on certain taxa such as snakes for which extinction risk may currently be underestimated due to lack of population information. Conservation actions specifically need to mitigate the effects of human-induced habitat loss and harvesting, which are the predominant threats to reptiles.

Max James Kohler papers, 1888-1934.

Contains scrapbooks, correspondence and reports relating to Kohler's extensive activities on behalf of liberal immigration and naturalization laws in the United States, his opposition to the registration of aliens, the problems of Chinese immigration to the United States, his opposition to the use of the term "Hebrew Race" in the classification of immigrants, the drafting of minority clauses at the Paris Peace Conference in 1919, Jewish and Christian relations in the U.S., and the condition of Jews in Russia, Roumania, Poland and Nazi-Germany with the following institutions: the American Civil Liberties Union, 1926-1934, the American Jewish Committee, 1909-1934, B'nai Brith, 1930-1933, the Union of American Hebrew Congregations - Board of Delegates on Civil Rights, the Committee on Ellis Island, the Foreign Language Information Service, the Hebrew Benevolent Society of Baltimore, the Hebrew Sheltering and Immigrant Aid Society, the Jewish Immigrants' Information Bureau in Galveston, Texas, the Industrial Removal Office, the National Conference of Jews and Christians, the National Council of Jewish Women, the National Council on Naturalization and Citizenship, the Bureau of Immigration to the United States Department of Laborm the United States Department of Commerce and Labor, the Department of State and individual United States Congressmen.

Franks family papers, 1711-1821, [1965-1968].

Contains business correspondence, accounts and documents relating to Jacob Franks of New York, his two sons, Moses and David, a nephew, Isaac, and a John Franks of Halifax, possibly a member of the family.

Names of boys and girls in the K.K.S.I school, March 8, 1795. Report of the School Committee, February 2, 1794

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Letter to trustees of K.K.S.I. from James Foster, regarding his desire to become a Jew

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Kutsu kuuliaisuuteen : James I. Packerin liittonomistinen raamattukäsitys

This dissertation examines James I. Packer s view of the Bible as the book of God s revelation. However, this study could not be complete without discussion of his background ideas about God, man and the foundations of theology. The research method used in this dissertation is systematic analysis. I analyse key theological concepts in the data, such as inerrancy, God s word and the covenant of grace, and examine Packer s concepts primarily in the context of the reformed tradition that he represents. Although the dissertation presents the philosophical premises of Packer s thought, the focus is on an analysis of theological concepts. Packer claims to approach theological issues broadly and to reject legalism. However, he also considers Calvinist thinking to be best suited to theological work and emphasises the central role of law in his view of the Bible. My dissertation pays particular attention to the status of law in Packer s theology and especially in the covenant of grace. The dissertation shows that the fundamental theological structure of Packer s view of the Bible is based on Puritan covenant theology, which consists of the temporally successive covenant of works and covenant of grace. Covenant theology stresses the connection and friendship between God and man. Man s highest goal according to the Westminster Confession of Faith (1647) is to glorify the triune God and to rejoice in him for all eternity. After the fall of man, this friendship between God and man can only take place in the covenant of grace. For Packer, the covenant of grace encompasses not only the time of the Gospel, but also the time of the law before the Gospel. Consequently, the covenant of grace incorporates in its very essence the demand of obedience to God s law. Covenant theology forms the foundation for both his view of the Bible and his idea that a believer lives in a covenant of grace, the key aspects of which are God s commandments and man s works. Law and the Gospel are not considered fundamental opposites in the covenant of grace, unlike in justification. In the covenant of grace, man has become God s friend who obeys the law as the law of Christ in a way which differs from Luther s view of obedience to the faith . For Packer, covenant theology is a Puritan instrument to link predestination and sanctification. Works committed in obedience show that the believer belongs to the covenant of grace and will be among the saved. Although voluntary obedience to God s commandments is not a direct instrument to achieve salvation, it is a pivotal sign of predestination. God calls the predestined to salvation with an effectual calling, the reliable message of the Bible. In sanctification, God guides a believer living in the context of covenantal nomism. In that sense, the Bible is above all an instrument of law guided by reason. In man s obedience, God completes man s nature and restores the imago Dei in man.

Comments on: "The role of the social environment in psychiatric research: Outstanding challenges and future directions by Dana March, James Kirkbride, Wim Veling"

On 17 March 2009, we hosted a live discussion of fresh new ideas in the epidemiology of schizophrenia. Discussion leaders Dana March of Columbia University, James Kirkbride of the University of Cambridge, and Wim Veling of Parnassia Psychiatric Institute delivered a wide-ranging discussion of social factors such as migration, ethnicity, and urbanicity, but also asked how this research could benefit from genetic insights. Finally, they discussed possible biological mechanisms that might transduce social factors into psychosis

Copy of 1794 bill of sale of the ship "Farmer"

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Directional dominance on stature and cognition in diverse human populations

Homozygosity has long been associated with rare, often devastating, Mendelian disorders1, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3, 4. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10−300, 2.1 × 10−6, 2.5 × 10−10 and 1.8 × 10−10, respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months’ less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5, 6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.