A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.Please refer to the manuscript or visit the publisher's website for funding infomation

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.Peer reviewe

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P <5 x 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.Peer reviewe

Characterization of Japanese soil-borne wheat mosaic virus movement protein and investigation of interacting host-plant factors

Das japanische bodenbürtige Weizenmosaik Furovirus (JSBWMV) infiziert neben Weizen auch Gerste. Es wird von dem obligaten Wurzelparasiten Polymyxa graminis übertragen. In Gerste sind sowohl gegen das Virus als auch gegenüber dem Vektor P. graminis keine Resistenzen bekannt. Um die Infektion des zweiteiligen RNA-Virus besser zu verstehen, wurde in dieser Arbeit die Wechselwirkung zwischen dem Virus und der Modellpflanze Nicotiana benthamiana untersucht. Die Ausbreitung des Virus von Zelle zu Zelle und über längere Distanzen ist wichtig für das Virus, um die Infektion zu etablieren. Um sich in der Pflanze verbreiten zu können, exprimieren Viren sogenannte „movement proteins“ (MP). Für das MP des JSBWMV, welches zur 30K MP-Familie gehört, wurde in dieser Arbeit eine Lokalisation an Plasmodesmen, den Zell-Zell Kontakten zwischen Pflanzenzellen und an Punkten in der Plasmamembran gezeigt, bei der ebenfalls eine Interaktion des MP mit sich selbst beobachtet wurde. Die Bedeutung von MPs für den interzellulären viralen Transport und Schutz der viralen RNA werden durch die Ergebnisse unterstützt. Um Erkenntnisse über die Interaktion zwischen dem JSBWMV MP und der pflanzlichen Zelle zu erlangen, wurden MP-interagierende RNAs und Proteine identifiziert. Für das JSBWMV MP wurden bindende RNA-Moleküle identifiziert, welche für potentielle Transkriptionsfaktoren kodieren. Zwei interagierende Proteine wurden mittels Massenspektrometrie gefunden und die Interaktion konnte in weiteren Experimenten bestätigt werden. Das „pentatricopeptiderepeat-containing Protein“ (PPR), gehört wahrscheinlich zur P-Klasse der PPR-Proteine. Für das N-terminal Fluoreszenz-markierte PPR wurde eine Lokalisation im Zytoplasma und an Plasmodesmen beobachtet, während für das C-terminal Fluoreszenz-markierte PPR eine chloroplastidäre Lokalisation gezeigt wurde. Das PPR-Protein spielt möglicherweise eine Rolle in der Regulation von mRNA in den Chloroplasten. Darauf deuten RNA-Immunpräzipitationen (RIPs) hin, in denen interagierende RNA-Moleküle identifiziert wurden. Das „heat shock protein 70“ (HSP70) gehört zu den Chaperonen und eine zytoplasmatische und eine Kern-Lokalisation konnte experimentell beobachtet werden. Eine erhöhte Expression vom HSP70 in N. benthamiana als Reaktion auf die über-Expression von JSBWMV MP wurde gezeigt. RIP-Experimente weisen auf die Rolle des HSP70 im pflanzlichen Immunsystem hin. Als Interaktionspartner von HSP70 als auch MPJSBWMV wurden beta-1,3-Glucosidase RNAs identifiziert. Beta-1,3-Glucosidasen sind Hauptakteure in der Regulation der Plasmodesma-Öffnungsweite und stellen einen Link zwischen den beiden Proteinen und Plasmodesmen her. Die erlangten Ergebnisse über die Wechselwirkung zwischen dem MP vom JSBWMV und den pflanzlichen Interaktionspartnern PPR und HSP70 geben Einblicke in das Infektionsgeschehen von JSBWMV. Die Erkenntnisse können in Zukunft dafür genutzt werden, neue Abwehrstrategien gegen das Virus in der Pflanze zu entwickeln. Diese Dissertation wurde nur als Druckausgabe veröffentlicht.The Japanese soil-borne wheat mosaic virus (JSBWMV) is a cereal virus infecting barley as well as wheat. The virus belongs to the genus Furovirus and is transmitted by the obligate biotrophic root parasite Polymyxa graminis. For the agriculturally important crop barley, no resistances against JSBWMV or its vector P. graminis are known. In this work the infection of the bipartite positive-stranded RNA virus JSBWMV was investigated to understand the interplay between the virus and the host-plant. Nicotiana benthamiana was used as model host. For the viral life cycle the movement of the virus over short distances as well as long distances is important to efficiently establish infection. Viruses encode “movement proteins” (MP) which facilitate the movement processes. For the JSBWMV MP, belonging to the 30K MP-family, a localization to plasmodesmata and to punctuate spots in the plasma membrane was observed. The importance of MPs for intercellular transport of viruses and protection of viral RNA are supported by these results. At both cellular localizations a self-interaction was revealed, which was not shown for a furoviral MP before. To understand the interplay of the virus with the plant cell, interacting RNA and proteins were identified using co-immunoprecipitation (IP) techniques. The experiments showed that the MP interacts with RNAs, which potentially encode transcription factors. Two interacting plant proteins were identified and the interaction was confirmed in further experiments. The potential P-type “pentatricopeptiderepeat-containing protein” (PPR) localized to two distinct subcellular localizations. The C-terminal tagged PPR localized to the chloroplast, while a distribution to the cytoplasm and to plasmodesmata was observed for the N-terminal tagged PPR. RNA-IPs identified interacting RNA-molecules and indicated that the PPR-protein possibly plays a role in regulating mRNA in the chloroplast. The “heat shock protein 70” (HSP70) is a chaperone and experiments displayed a cytoplasmic and nuclear localization. The protein is upregulated in response to the over-expression of the JSBWMV MP and RNA-IP-experiments highlight the role of HSP70 in the plant defense. Interestingly, RNAs interacting with both, MP and HSP70 allowed establishing a link between these two proteins and beta-1,3-glucosidase, one of the main regulators of plasmodesmata size exclusion limit. The results obtained for the JSBWMV MP and the host-plant interacting proteins PPR and HSP70 allow a deeper insight into the interaction of MP with the host cell in the viral infection. This knowledge may in the future be developed into new resistance strategies against JSBWMV. This dissertation was only published as a printed edition