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Many (digital) learning materials are often based on a combination of text and pictures, whereby pictures often only serve a decorative (learning-irrelevant) function. Such decorative pictures were proven as detrimental for learning success. In contrast, research on retrieval cues (also known as "memory cues") showed that a visual-semantic connection between the learning information and additional pictures might help to foster later retrieval processes. This experimental series tested if decorative pictures might serve as a retrieval enhancer. For this, four experiments (n[subscript 1] = 104, n[subscript 2] = 124, n[subscript 3] = 161, n[subscript 4] = 176) were conducted where a learning video about concepts in marketing was used with and without decorative pictures. In a subsequent learning test (retention and transfer questions) with or without these corresponding decorative pictures, the memory cue effect was examined. Besides, mental load and mental effort, as well as intrinsic motivation were measured. Across all experiments, results showed that the groups with decorative pictures which were only shown in the video performed significantly worse than the other groups (seductive detail effect). Moreover, students with decorative pictures in both the learning and the retrieval phase were found to learn more than groups without decorative pictures (memory cue effect). Significant moderators of this effect were found in the salience of the cues, the associative connection between the cues and the learning information, and the modality of the cues (visual vs. verbal). Results were explained by differences in cognitive and motivational variables.

When people attribute human characteristics to nonhuman objects they are amenable to anthropomorphism. For example, human faces or the insertion of personalized labels are found to trigger anthropomorphism. Two studies examine the effects of these features when included in decorative pictures in multimedia learning materials. In a first experiment, 81 university students were randomly assigned to 1 cell of a 2 (human faces vs. no faces in pictures) × 2 (personalized vs. nonpersonalized labels of pictures) between-subjects, factorial design. In addition to learning performance, cognitive, motivational, and emotional impacts of anthropomorphism are examined. Results show that both human faces and anthropomorphic labels were able to increase the learning performance on cognitive assessments. However, only human faces were able to influence motivational and emotional ratings significantly. In a second experiment, 108 secondary school students were randomly assigned to 3 groups (anthropomorphized pictures, nonanthropomorphized pictures, and no pictures) in order to evaluate possible advantages of anthropomorphism in decorative pictures in learning materials. Results show again that anthropomorphized pictures are better for learning than nonanthropomorphized pictures and also better than a control group. Results are discussed in the light of a debate on the inclusion or exclusion of decorative pictures.

Outbreaks of infectious diseases repeatedly affected medieval Europe, leaving behind a large number of dead often inhumed in mass graves. Human remains interred in two burial pits from 14th century CE Germany exhibited molecular evidence of Salmonella enterica Paratyphi C (S. Paratyphi C) infection. The pathogen is responsible for paratyphoid fever, which was likely the cause of death for the buried individuals. This finding presented the unique opportunity to conduct a paratyphoid fever association study in a European population. We focused on HLA-DRB1*03:01 that is a known risk allele for enteric fever in present-day South Asians. We generated HLA profiles for 29 medieval S. Paratyphi C cases and 24 contemporaneous controls and compared these to a modern German population. The frequency of the risk allele was higher in the medieval cases (29.6%) compared to the contemporaneous controls (13%; p = 0.189), albeit not significantly so, possibly because of small sample sizes. Indeed, in comparison with the modern controls (n = 39,689 ; 10.2%; p = 0.005) the frequency difference became statistically significant. This comparison also suggested a slight decrease in the allele's prevalence between the medieval and modern controls. Up to now, this is the first study on the genetic predisposition to Salmonella infection in Europeans and the only association analysis on paratyphoid fever C. Functional investigation using computational binding prediction between HLA variants and S. Paratyphi and S. Typhi peptides supported a reduced recognition capacity of bacterial proteins by DRB1*03:01 relative to other common DRB1 variants. This pattern could potentially explain the disease association. Our results suggest a slightly reduced predisposition to paratyphoid fever in modern Europeans. The causative allele, however, is still common today, which can be explained by a trade-off, as DRB1*03:01 is protective against infectious respiratory diseases such as severe respiratory syndrome (SARS). It is thus possible that the allele also provided resistance to corona-like viruses in the past. [ABSTRACT FROM AUTHOR]

Extracellular ice formation as a dehydrating agent is generally acknowledged as an important element of freezing avoidance in frost hardy plants, preventing the development of lethal ice crystals within living cells. While many reports on extracellular ice formation do exist for vascular plants, not much is known on ice formation for liverworts. In this study, ice formation was studied for two liverwort species occurring in climate zones with winter freezing, Conocephalum salebrosum and Marchanthia polymorpha L. subsp. ruderalis, together with taxon-specific ice nucleating temperature and seasonal concentration of ice nucleating agents. Samples were collected in late autumn from various sites in south west Germany. Afterwards the collected liverwort specimen were cultivated and acclimated in pots in the inner courtyard of the State Museum of Natural History Stuttgart, Germany. Ice formation was observed in the environmental scanning electron microscope (ESEM) within the air chambers of both species, with ice crystals growing out of the air chamber pores, as well as random ice crystal formation on various sites on the ventral side for both taxa. The growing ice sheets led to dehydration particularly of the parenchymatous cells. For both taxa, the observations support the relevance of extracellular ice formation for surviving freezing conditions but the experiments also indicate a better adaptation of C. salebrosum to frost. [ABSTRACT FROM AUTHOR]

Biogas plants enable power to be generated in a flexible way so that variable, renewable energy sources can be integrated into the energy system. In Germany, the Renewable Energy Sources Act promotes flexible power generation in biogas plants. Two existing biogas plants in flexible operation were analyzed with respect to economic viability and greenhouse gas (GHG) emissions to assess the feasibility of flexible operation. To do this, a biogas technology simulation model was developed to reproduce the technical design of both biogas plants and to link this design with twelve flexibilization scenarios. The evaluation of the economic viability is based on a discounting method of investment appraisal. For assessing the level of GHG emissions, the life cycle assessment method has been applied. The results show that the profitability of flexibilization is contingent upon premium payments promoting flexibility and direct sales resulting from a higher electrical efficiency of new or additionally installed combined heat and power units. Overall, with respect to profitability, the results of the flexible power generation scenarios are dependent upon the properties of the technical plant, such as its power generation and gas storage capacities. Relative GHG emissions from flexible biogas plants show significantly lower values than for referenced fossil gas-steam power stations. Among the various scenarios, the results reveal that the level of GHG emissions especially depends on the number of operating hours of the additional combined heat and power unit(s). The results of the analyzed biogas plants showed no direct correlation between GHG emissions and the economic benefits. Overall, a flexible power generation of biogas plants may improve the economic viability as well as result in lower GHG emissions in comparison with a conventional base load operation. © 2016 The Authors. International Journal of Energy Research published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The present study examined the role of politeness in instructions during learning with a multimedia web page. By incorporating former studies of the politeness effect, this study provides new insights into a possible operationalization of politeness for instructional messages. Based on a two-sided view (direct vs. polite), one hundred and twenty German upper secondary school students learned all about attribution theories while clicking through a learning web page where only instructional pages differed. The students were randomly assigned to one cell of a 2 (direct vs. polite) × 2 (on-screen vs. auditory) between-subjects factorial design. Results confirm the politeness effect for retention and transfer performances, showing large effect sizes. Students reported significantly higher scores on interest, probability of success, and learning assistance in the polite treatment group while scores on directness, restriction of freedom, extraneous cognitive load, and mental effort are significantly lower, however, no interaction was found for modality and politeness. Additionally, polite variations were not assessed as social cues. For this, a new term of cultural cues in multimedia learning is proposed. [ABSTRACT FROM AUTHOR]

Drug consumption and gambling are regarded as morality policies, especially in the American literature. Both are perceived as sinful and treated accordingly. This highly generalized assessment is rarely analysed systematically in a non-American context. Therefore, we investigate whether these policies are indeed framed morally and if this framing is stable over time in two European countries. Next, we analyse whether shifts in morality framing have consequences for regulation. In this way,we contribute to the literature on morality policies, particularly the ways in which these policies are defined and empirically identified. We identify morality policies based on how actors frame issues rather than by policies' substantive content. We show that the morality framing was once prominent but has lost its importance over time, and we find a close connection between frame shifts and policy output, although this is not a uniform development and does not characterize all cases. [ABSTRACT FROM PUBLISHER]

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The transition from hunting and gathering to agriculture in Europe is associated with demographic changes that may have shifted the human gene pool of the region as a result of an influx of Neolithic farmers from the Near East. However, the genetic composition of populations after the earliest Neolithic, when a diverse mosaic of societies that had been fully engaged in agriculture for some time appeared in central Europe, is poorly known. At this period during the Late Neolithic (ca. 2,800-2,000 BC), regionally distinctive burial patterns associated with two different cultural groups emerge, Bell Beaker and Corded Ware, and may reflect differences in how these societies were organized. Ancient DNA analyses of human remains from the Late Neolithic Bell Beaker site of Kromsdorf, Germany showed distinct mitochondrial haplotypes for six individuals, which were classified under the haplogroups I1, K1, T1, U2, U5, and W5, and two males were identified as belonging to the Y haplogroup R1b. In contrast to other Late Neolithic societies in Europe emphasizing maintenance of biological relatedness in mortuary contexts, the diversity of maternal haplotypes evident at Kromsdorf suggests that burial practices of Bell Beaker communities operated outside of social norms based on shared maternal lineages. Furthermore, our data, along with those from previous studies, indicate that modern U5-lineages may have received little, if any, contribution from the Mesolithic or Neolithic mitochondrial gene pool. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sd USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans. [ABSTRACT FROM AUTHOR]

Goal, Scope and Background. The goal of the study is a life cycle assessment according to ISO 14040–14043 for wood floor coverings (solid parquet, multilayer parquet, solid floor board and wood blocks). The representative study covers approximately 70% of all wood flooring production in Germany. The comparison of the floor coverings among each other was not the aim. Instead the study provides basic data for all wood floor coverings for a possible comparison with other floor coverings later on. The main focus was a hot spot analysis to help the involved industry partners to improve their environmental performance, and to use the results for marketing purposes. Inventory Analysis. The study covers the whole life cycle from forest management, sawmilling, manufacturing, laying and surface finishing through to refurbishment and end-of-life. The end-of-life scenario is the thermal utilisation of the floor coverings. The energy gained in the end-of-life scenario is accounted for by system expansion (avoided burden approach). Impact Assessment. In the Impact Assessment the following categories were considered: global warming (GWP), acidification (AP), eutrophication (EP), ozone depletion (ODP) and photo-oxidant formation (POCP) following the CML baseline 2000 method. Furthermore the use of primary energy is presented. The low emissions of greenhouse gases during the life cycle can lead to a negative contribution to the global warming potential if more emissions are avoided through the substitution process than are emitted during the life cycle of the product. Mainly energy consumption and the use of solvents influence the environmental impacts of the systems under analysis. The most relevant unit processes for the issue of energy consumption are ‘production’ and for photo-oxidant formation ‘laying’, ‘surface finishing’ and ‘refurbishment’. These are therefore the unit processes with the greatest potential for improvement. Normalisation and Sensitivity Analysis. The normalisation results show that the photo-oxidant formation potential is most significant in comparison to the other impact categories. Improvement options and the choice of the functional unit have been further explored in a sensitivity analysis. Discussion and Conclusions. The most important opportunities for improvements are located in the unit processes laying, surface finishing and refurbishment. The POCP result can be reduced significantly depending on the choice of glue and varnish at each of these stages. The results of the sensitivity analysis showed a potential for improvement in this category. No data for the production of an oil and wax finish was available. This option would be interesting to consider at in a further study. The time aspect of storing CO2 for a period of time is not considered in this paper, but will be addressed in a forthcoming paper (Nebel and Cowell 2003). [ABSTRACT FROM AUTHOR]

Background: Due to the increase in survival rates for congenital heart disease (CHD) in the last decades, over 90% of patients today reach adulthood. Currently, there are more than 300,000 adults with CHD (ACHD) living in Germany. They have an increased need for specialized medical care, since almost all ACHD have chronic heart disease and suffer from specific chronic symptoms, risks, and sequelae. Primary care physicians (PCPs) play a crucial role in referring patients to ACHD specialists or specialized institutions. This cross-sectional study is intended to clarify the real-world care of ACHD from the PCP's perspective. Methods: This analysis, initiated by the German Heart Centre Munich, was based on a 27-item questionnaire on actual ACHD health care practice in Germany from the PCP's perspective. Results: In total, 767 questionnaires were considered valid for inclusion. The majority of the PCPs were general practitioners (95.9%), and 84.1% had cared for ACHD during the past year. A majority (69.2%) of the PCPs had cared for patients with simple CHD, while 50.6% and 33.4% had cared for patients with moderate and severe CHD, respectively, in all age groups. PCPs treated almost all typical residual symptoms and sequelae, and advised patients regarding difficult questions, including exercise capacity, pregnancy, genetics, and insurance matters. However, 33.8% of the PCPs did not even know about the existence of certified ACHD specialists or centers. Only 23.9% involved an ACHD-specialized physician in their treatment. In cases of severe cardiac issues, 70.8% of the PCPs referred patients to ACHD-certified centers. Although 52.5% of the PCPs were not sufficiently informed about existing structures, 64.2% rated the current care situation as either "very good" or "good". Only 26.3% (n = 190) of the responding physicians were aware of patient organizations for ACHD. Conclusions: The present study showed that the majority of PCPs are not informed about the ACHD care structures available in Germany. The need for specialized ACHD follow-up care is largely underestimated, with an urgent need for optimization to reduce morbidity and mortality. For the future, solutions must be developed to integrate PCPs more intensively into the ACHD care network. [ABSTRACT FROM AUTHOR]

Ancient DNA research has focused on the genetic patterns of the earliest farmers during the European Neolithic, especially with regards to the demographic changes in the transition from hunting and gathering to agriculture. However, genetic data is relatively lacking after this earliest transition period, when societies had fully adapted to new agrarian lifestyles specific to their local environment. During the later central European Neolithic (ca. 3600–2800 cal BC), large-scale collective burials and monumental architecture appeared within the landscape of many agricultural societies. This phenomenon has been argued to represent the emergence of a “collective” identity. With the aim of exploring genetic-based relations among individuals collectively buried, we obtained human skeletal remains of nearly 200 individuals from four later Neolithic collective burial sites in Germany: Calden, Odagsen, Groβenrode, and Panker. We successfully reproduced reliable mitochondrial DNA (mtDNA) haplotypes from eight Neolithic individuals, which were assigned to haplogroups H, HV0, and X2. Shared haplotypes observed among individuals within Calden and Odagsen suggest that genetic relations may have shaped the arrangement of the deceased within later Neolithic agricultural groups. [ABSTRACT FROM AUTHOR]

The reconstruction and understanding of tipping points in environmental systems have become an important issue for the global geoscientific community. This study focuses on the reconstruction of the Holocene deposition history of the Loosbach valley at the Pestenacker site, a Late Neolithic wetland occupation in the northern Alpine forelands of Central Europe (South Germany). Since 2011, it has been part of the UNESCO World Heritage 'Prehistoric pile dwellings around the Alps'. This study aims to reconstruct a potential passing of a Middle Holocene hydrological tipping point in the Loosbach valley and its interrelation with the Late Neolithic onset of valley occupation at that time. In this context, we make use of chronostratigraphical data sets about the Holocene fluvial dynamics of Loosbach stream from available archaeological excavation reports and spatially enlarge the local model of Holocene stream evolution with high-resolution direct push cross-sections from the proximate fen stratigraphies. As a result, the onset of the Late Neolithic settlement phase corresponds with a local hydrological tipping point at the wetland site of Pestenacker. Increased cooling and climatic humidity led to stream incision into the valley floor that resulted in draining, a local decrease of the groundwater table and the end of fen formation. As an apparently contradictory result of this process, increased water availability and run-off correspond with increased edaphic aridity on the valley floor. The latter may have made it possible to settle the valley floor during the late Neolithic. • Direct push sensing shows tripartite lithostratigraphy near Pestenacker wetland site. • Mid-Holocene cooling and increased humidity resulted in the onset of channel flow. • Stream incision led to fen draining, groundwater lowering & enhanced edaphic aridity. • Late-Neolithic wetland occupation of Pestenacker site as a possible consequence. [ABSTRACT FROM AUTHOR]

Yersinia pestis has been infecting humans since the Late Neolithic (LN). Whether those early infections were isolated zoonoses or initiators of a pandemic remains unclear. We report Y. pestis infections in two individuals (of 133) from the LN necropolis at Warburg (Germany, 5300-4900 cal BP). Our analyses show that the two genomes belong to distinct strains and reflect independent infection events. All LN genomes known today (n = 4) are basal in the phylogeny and represent separate lineages that probably originated in different animal hosts. In the LN, an opening of the landscape resulted in the introduction of new rodent species, which may have acted as Y. pestis reservoirs. Coincidentally, the number of dogs increased, possibly leading to Y. pestis infections in canines. Indeed, we detect Y. pestis in an LN dog. Collectively, our data suggest that Y. pestis frequently entered human settlements at the time without causing significant outbreaks., (© 2024. The Author(s).)

The Wartberg culture (WBC, 3500-2800 BCE) dates to the Late Neolithic period, a time of important demographic and cultural transformations in western Europe. We performed genome-wide analyses of 42 individuals who were interred in a WBC collective burial in Niedertiefenbach, Germany (3300-3200 cal. BCE). The results showed that the farming population of Niedertiefenbach carried a surprisingly large hunter-gatherer ancestry component (34-58%). This component was most likely introduced during the cultural transformation that led to the WBC. In addition, the Niedertiefenbach individuals exhibited a distinct human leukocyte antigen gene pool, possibly reflecting an immune response that was geared towards detecting viral infections.

The hepatitis B virus (HBV) is one of the most widespread human pathogens known today, yet its origin and evolutionary history are still unclear and controversial. Here, we report the analysis of three ancient HBV genomes recovered from human skeletons found at three different archaeological sites in Germany. We reconstructed two Neolithic and one medieval HBV genome by de novo assembly from shotgun DNA sequencing data. Additionally, we observed HBV-specific peptides using paleo-proteomics. Our results demonstrated that HBV has circulated in the European population for at least 7000 years. The Neolithic HBV genomes show a high genomic similarity to each other. In a phylogenetic network, they do not group with any human-associated HBV genome and are most closely related to those infecting African non-human primates. The ancient viruses appear to represent distinct lineages that have no close relatives today and possibly went extinct. Our results reveal the great potential of ancient DNA from human skeletons in order to study the long-time evolution of blood borne viruses., Competing Interests: BK, JS, FK, DK, EB, AI, CR, SK, DY, SF, HH, TM, SL, HM, SF, NN, KA, SS, AT, AH, AN, JK No competing interests declared, (© 2018, Krause-Kyora et al.)

Human pigmentation traits are of great interest to many research areas, from ancient DNA analysis to forensic science. We developed a gene-based predictive model for pigmentation phenotypes in a realistic target population for forensic case work from Northern Germany and compared our model with those brought forth by previous studies of genetically more heterogeneous populations. In doing so, we aimed at answering the following research questions: (1) do existing models allow good prediction of high-quality phenotypes in a genetically similar albeit more homogeneous population? (2) Would a model specifically set up for the more homogeneous population perform notably better than existing models? (3) Can the number of markers included in existing models be reduced without compromising their predictive capability in the more homogenous population? We investigated the association between eye, hair and skin colour and 12 candidate single-nucleotide polymorphisms (SNPs) from six genes. Our study comprised two samples of 300 and 100 individuals from Northern Germany. SNP rs12913832 in HERC2 was found to be strongly associated with blue eye colour (odds ratio=40.0, P<1.2 × 10(-4)) and to yield moderate predictive power (AUC: 77%; sensitivity: 90%, specificity: 63%, both at a 0.5 threshold for blue eye colour probability). SNP associations with hair and skin colour were weaker and genotypes less predictive. A comparison with two recently published sets of markers to predict eye and hair colour revealed that the consideration of additional SNPs with weak-to-moderate effect increased the predictive power for eye colour, but not for hair colour.

Genetic factors have been estimated to account for about 25% of the variation in an adult's life span. The complement component C4 with the isotypes C4A and C4B is an effector protein of the immune system, and differences in the overall C4 copy number or gene size (long C4L; short C4S) may influence the strength of the immune response and disease susceptibilities. Previously, an association between C4B copy number and life span was reported for Hungarians and Icelanders, where the C4B*Q0 genotype, which is defined by C4B gene deficiency, showed a decrease in frequency with age. Additionally, one of the studies indicated that a low C4B copy number might be a genetic trait that is manifested only in the presence of the environmental risk factor "smoking". These observations prompted us to investigate the role of the C4 alleles in our large German longevity sample (∼ 700 cases; 94-110 years and ∼ 900 younger controls). No significant differences in the number of C4A, C4B and C4S were detected. Besides, the C4B*Q0 carrier state did not decrease with age, irrespective of smoking as an interacting variable. However, for C4L*Q0 a significantly different carrier frequency was observed in the cases compared with controls (cases: 5.08%; controls: 9.12%; p = 0.003). In a replication sample of 714 German cases (91-108 years) and 890 controls this result was not replicated (p = 0.14) although a similar trend of decreased C4L*Q0 carrier frequency in cases was visible (cases: 7.84%; controls: 10.00%).

In addition to APOE and FOXO3, AKT1 has recently been suggested as a third consistent longevity gene, with variants in AKT1 found to be associated with human lifespan in two previous studies. Here, we evaluated AKT1 as a longevity-associated gene across populations by attempting to replicate the previously identified variant rs3803304 as well as by analyzing six additional AKT1 single-nucleotide polymorphisms, thus capturing more of the common variation in the gene. The study population was 2996 long-lived individuals (nonagenarians and centenarians) and 1840 younger controls of Danish and German ancestry. None of the seven SNPs tested were significantly associated with longevity in either a case-control or a longitudinal setting, although a supportive nominal indication of a disadvantageous effect of rs3803304 was found in a restricted group of Danish centenarian men. Overall, our results do not support AKT1 as a universal longevity-associated gene.

In this study, we investigated 102 single-nucleotide polymorphisms (SNPs) covering the common genetic variation in 16 genes recurrently regarded as candidates for human longevity: APOE; ACE; CETP; HFE; IL6; IL6R; MTHFR; TGFB1; APOA4; APOC3; SIRTs 1, 3, 6; and HSPAs 1A, 1L, 14. In a case-control study of 1,089 oldest-old (ages 92-93) and 736 middle-aged Danes, the minor allele frequency (MAF) of rs769449 (APOE) was significantly decreased in the oldest-old, while the MAF of rs9923854 (CETP) was significantly enriched. These effects were supported when investigating 1,613 oldest-old (ages 95-110) and 1,104 middle-aged Germans. rs769449 was in modest linkage equilibrium (R (2)=0.55) with rs429358 of the APOE-ε4 haplotype and adjusting for rs429358 eliminated the association of rs769449, indicating that the association likely reflects the well-known effect of rs429358. Gene-based analysis confirmed the effects of variation in APOE and CETP and furthermore pointed to HSPA14 as a longevity gene. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, only one SNP, rs2069827 (IL6), was borderline significantly associated with survival from age 92 (P-corrected=0.064). This advantageous effect of the minor allele was supported when investigating a Dutch longitudinal cohort (N=563) of oldest-old (age 85+). Since rs2069827 was located in a putative transcription factor binding site, quantitative RNA expression studies were conducted. However, no difference in IL6 expression was observed between rs2069827 genotype groups. In conclusion, we here support and expand the evidence suggesting that genetic variation in APOE, CETP, and IL6, and possible HSPA14, is associated with human longevity.

Rationale: Sarcoidosis is a complex inflammatory disease with a heterogeneous clinical picture. Among others, an acute and chronic clinical course can be distinguished, for which specific genetic risk factors are known., Objectives: To identify additional risk loci for sarcoidosis and its acute and chronic subforms, we analyzed imputed data from a genome-wide association scan for these phenotypes., Methods: After quality control, the genome-wide association scan comprised nearly 1.3 million imputed single-nucleotide polymorphisms based on an Affymetrix 6.0 Gene Chip dataset of 564 German sarcoidosis cases, including 176 acute and 354 chronic cases and 1,575 control subjects., Measurements and Main Results: We identified chromosome 11q13.1 (rs479777) as a novel locus influencing susceptibility to sarcoidosis with genome-wide significance. The marker was significantly associated in three distinct German case-control populations and in an additional German family sample with odds ratios ranging from 0.67 to 0.77. This finding was further replicated in two independent European case-control populations from the Czech Republic (odds ratio, 0.75) and from Sweden (odds ratio, 0.79). In a meta-analysis of the included European case-control samples the marker yielded a P value of 2.68 × 10(-18). The locus was previously reported to be associated with Crohn disease, psoriasis, alopecia areata, and leprosy. For sarcoidosis, fine-mapping and expression analysis suggest KCNK4, PRDX5, PCLB3, and most promising CCDC88B as candidates for the underlying risk gene in the associated region., Conclusions: This study provides striking evidence for association of chromosome 11q13.1 with sarcoidosis in Europeans, and thus identified a further genetic risk locus shared by sarcoidosis, Crohn disease and psoriasis.

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET., Methods: Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET., Results: We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10(-5), odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10(-3), OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10(-10), OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087., Conclusions: We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.

The gene tyrosine hydroxylase 1 (TH01) has been suggested as a candidate for human longevity. A previous study has shown an association between longevity and specific alleles of the TH01 short tandem repeat (STR) polymorphism in an Italian population. This STR locus is also widely used in forensic genetics. If the TH01-longevity association could be confirmed in independent samples, this finding would have important ramifications for the use of this polymorphism in a forensic context. In the present study, we sought to replicate the previous association result by investigating 471 long-lived individuals (96-110 years) and 462 younger controls (19-75 years) from Germany. In the analyzed samples, the association between TH01 and longevity was not replicated. However, the obtained TH01 allele frequencies were consistent with published data. We observed considerable differences in the allele distribution between Germans and Italians, in particular with regard to allele 9.3, which displayed a previously undetected decreasing West-East and North-South cline across Europe. The discrepant TH01-longevity association results in Germans and Italians could therefore be due to population-specific effects. This finding highlights the need to take into consideration population genetic data when dealing with association studies.

In mammals, the forkhead box class O (FOXO) family of transcription factors consists of the four members FOXO1, FOXO3A, FOXO4, and FOXO6. The FOXO genes are homologues of daf-16, a key regulator of the insulin-IGF1 signaling pathway and a modulator of lifespan in Caenorhabditis elegans. Recently, variants in FOXO3A have consistently been associated with human longevity in various populations worldwide. Given this confirmed finding, it is conceivable that polymorphisms in the other FOXO genes might have a similar effect on human longevity. To evaluate whether allelic variation in FOXO1, FOXO4, and FOXO6 influences the ability to become long-lived, we performed a comprehensive haplotype-tagging analysis of the three genes in a group of 1447 centenarians/nonagenarians and 1029 younger controls from Germany. This is the first investigation to analyze a possible association of human longevity with FOXO4 and FOXO6, respectively, and the largest and most comprehensive study to date to assess the genetic contribution of FOXO1 to the phenotype. Our results suggest that in Germans, none of the three genes plays a significant role in the ability to reach old age. With regard to FOXO1, this observation is supported by data from an Italian sample and is consistent with several previous reports, but appears to be in contrast to a recent study of Han Chinese. The discrepant association findings in Europeans and Chinese may be explained by their different FOXO1 linkage disequilibrium structures and could indicate a Chinese- or Asian-specific effect., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8×10(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele ɛ4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.

The genetic causes of essential tremor (ET) seem to be heterogeneous. Recently, ET has been found associated with a functional variant (Ser9Gly) of the dopamine D(3) receptor (DRD3), located in the ETM1 locus on chromosome 3q13.3 described for the first time in 1997. We examined this variant in three different populations from Germany, Denmark and France. We undertook an association study of the Ser9Gly variant in 202 cases with a familial history from unrelated families with ET, 97 cases with isolated non-familial ET and 528 healthy controls. In addition, linkage and segregation analyses were carried out in 22 ET families. The distribution of genotypes and allele frequencies showed no significant differences in the whole sample and in a subanalysis of familial and sporadic cases. Age at onset of tremor, tremor duration and tremor severity did not show an association with the genotype. In addition, the DRD3 variant was not found linked to the disease in a subset of informative ET families. We did not find a significant association of the DRD3 variant with ET nor linkage to the DRD3 receptor in German, Danish and French ET patients and families, suggesting that it is unlikely to be a causal factor for ET.

Background: Triosephosphate isomerase (TPI) is a central and conserved glycolytic enzyme. In humans, TPI is encoded by a single gene on 12p13, and associated with a rare genetic disorder, TPI deficiency. Reduced TPI activity can increase specific oxidant resistances of model organisms and TPI null-alleles have been hypothesized to promote a heterozygote advantage in man. However, comprehensive genetic information about the TPI1 locus is still lacking., Results: Here, we sequenced the TPI1 locus in a sample of 357 German long-lived individuals (LLI) aged 95 to 110 years. We identified 17 different polymorphisms, of which 15 were rare and previously unknown. The two remaining SNPs occurred at much higher frequency and were tested for association with the longevity phenotype in larger samples of LLI (n = 1422) and younger controls (n = 967). Neither of the two markers showed a statistically significant difference in allele or genotype frequency between LLI and control subjects., Conclusion: This study marks the TPI1 locus as extraordinarily conserved, even when analyzing intronic and non-coding regions of the gene. None of the identified sequence variations affected the amino acid composition of the TPI protein and hence, are unlikely to impact the catalytic activity of the enzyme. Thus, TPI variants occur less frequent than expected and inactive alleles are not enriched in German centenarians.

C-C chemokine receptors have been suggested to play an important role in sarcoidosis pathogenesis. Previous investigation of the C-C chemokine receptor 5 (CCR5) gene revealed the association of the HHC haplotype with "persistent lung involvement" in two European sarcoidosis populations. Based on this finding, we investigated a possible association of the HHC haplotype and its marker alleles in an extended German sarcoidosis sample that comprised 995 German sarcoidosis families including individuals with the chronic and acute form of the disease, further refined to patients with and without Löfgren's syndrome. We genotyped this sample and 538 healthy control subjects for 8 single nucleotide polymorphisms (SNPs) that define the HHC haplotype in the CCR5 genomic region. Analysis of 3 sarcoidosis phenotypes (chronic, acute and Löfgren's syndrome) revealed that the HHC haplotype was not associated with chronic sarcoidosis although a substantial overlap can be assumed between the chronic form examined in our study and "persistent parenchymal lung involvement", the phenotype for which an association was previously established. However, 2 marker alleles in the putative CCR5 promoter, which are part of the HHC haplotype, are associated with Löfgren's syndrome. Strikingly, the association is restricted to females. This finding is consistent with recently described sex-specific manifestations of Löfgren's syndrome and with previous functional studies suggesting an estrogen-dependent CCR5 expression. The female-specific association of SNPs in the putative CCR5 promoter region with Löfgren's syndrome raises the possibility that the dysregulated, sex-specific modification of CCR5 expression could contribute to the increased risk of women to develop the disease.

Recently, the C-allele of polymorphism rs2359612 (VKORC1: c.283+837C>T) in the VKORC1 gene has been reported to represent a major risk factor for coronary heart disease (CHD), stroke, and aortic dissection in Chinese patients. VKOR activity itself is the rate-limiting step in gamma-carboxylation of vitamin K-dependent coagulation factors (factors II, VII, IX, X, protein C, S, and Z) and proteins of calcium metabolism (matrix Gla protein and osteocalcin). Gamma-carboxylation is essential for the biological activity of these proteins that have been previously hypothesised to play a role in the pathogenesis of atherosclerosis. It was the objective of this study to analyse the VKORC1 genotype frequency in patients with CHD and controls from Northern Germany and to investigate the association of VKORC1 and CHD risk in patients with an European background. CHD patients (n = 901) and healthy controls (n = 521) were part of the PopGen biobank. Case and control samples were matched for ethnic and geographic origin, age and gender. After typing German CHD patients and control individuals, no evidence for a statistically significant association was detected between VKORC1 genotype and CHD phenotype. Also stratification for gender and myocardial infarction yielded no significant results. In conclusion, the discrepant association findings in Chinese and German populations may be explained by ethnic differences in genetic and perhaps environmental predisposition, modifying the polygenic CHD phenotype by interacting with VKORC1 variants and thus conferring disease susceptibility in some populations, but not in others.

In a previous study on Sicilian men, an association of the functional polymorphism Asp299Gly in the TLR4 gene was reported with longevity and a reduced risk of myocardial infarction (MI). Here, we sought to confirm the findings in our extensive collection of 273 long-lived men (95-107 years), 606 male early-onset MI patients and 594 appropriate controls from Germany. Despite sufficient statistical power to replicate the findings observed in the South Italians, our results rule out a noteworthy influence of the TLR4 polymorphism upon human longevity or MI in German men. Therefore, the previously described associations in Sicilians might reflect either population-specific or potentially false-positive results.

We sought to verify whether variation in the promoter of the gene encoding placental anticoagulant protein annexin A5 (ANXA5) represents a risk factor for recurrent pregnancy loss (RPL). Sequence analysis of 70 German RPL patients, all known to carry neither factor V Leiden nor a prothrombin mutation, revealed four consecutive nucleotide substitutions in the ANXA5 promoter, which were transmitted as a joint haplotype (M2). Reporter gene assays revealed that M2 reduces the in vitro activity of the ANXA5 promoter to 37-42% of the normal level. The possible relationship between M2 and RPL was evaluated by comparing RPL patients with two independent control groups recruited from the registry of the Institut für Humangenetik in Münster and the PopGen biobank in Kiel, respectively. Carriers of M2 were found to exhibit a > 2-fold higher RPL risk than non-carriers (odds ratio, 2.42; 95% confidence interval, 1.27-4.58) when using unselected controls (PopGen) and an almost 4-fold higher risk when using the Münster 'super-controls', i.e. women with successful pregnancies and no previous history of pregnancy losses (odds ratio, 3.88; 95% confidence interval, 1.98-7.54). This statistically significant association should facilitate the development of improved prognostic algorithms for RPL, involving a more precise assessment of individual disease risks, and provide a guide to offering adequate therapies where relevant.

The functional single nucleotide polymorphism rs1801274 in the FCGR2A gene (His131Arg) influences the efficiency of hIgG2 binding, the main isotype produced in response to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. In contrast to the receptor with the His131 allele, FcgammaRIIa-Arg131 binds hIgG2 poorly and carriers of this variant have been shown to be much more susceptible to succumb to bacterial pneumonia or meningitis. As bacteraemic pneumonia is one of the leading causes of death in elderly individuals, we hypothesized that the Arg131 variant could be a major mortality factor in the old. We analysed the FCGR2A-His131Arg polymorphism in a group of 408 German centenarians and two samples of younger Germans aged 60-75 and 18-49 years, respectively. No statistically significant differences were observed between the three age groups, neither at the allele nor at the genotype level. Apparently, the ability to reach old age is largely unaffected by the genetically determined efficacy of the FCGR2A-based immune response. However, the severely reduced ability of FCGR2A-131Arg carriers to eliminate encapsulated bacteria must apparently be compensated by an alternative mechanism, possibly involving other genetic survival factors.

Infection and innate immunity have been suggested as playing an important role in the pathogenesis of atherosclerosis. The recently discovered pattern-recognition receptor (PRR) proteins initiate signalling after host-pathogen interactions and several PRRs, especially the Toll-like receptor 4 (TLR4), have been shown to be involved in the development and progression of atherosclerosis. A new addition to the PRRs is CARD4, a gene that encodes the protein nucleotide-binding oligomerization domain 1 (NOD1) and that seems to be associated with barrier function in chronic inflammatory disorders. Recently, a functional variant in the CARD4 gene, the insertion-deletion polymorphism ND(1)+32656, has been associated with inflammatory barrier diseases (inflammatory bowel diseases and asthma). We analysed the frequencies of this known functional mutation in the CARD4 gene and of the two adjacent variants, rs2075822 and rs2907748, in a German sample of 1440 unrelated early onset coronary heart disease (CHD) patients and healthy controls. Genotype and haplotype data showed no evidence for a significant association of these CARD4 variants with CHD. Our results suggest that the analysed CARD4 mutations do not play a major role in the aetiology of CHD.

Human longevity is a multifactorial condition with a significant genetic contribution. A recent association study in two independent samples of long-lived U.S. Caucasians [long-lived individuals (LLI)] identified a SNP haplotype of the microsomal triglyceride transfer protein (MTP, 4q25) that was underrepresented among LLI when compared with younger controls. This suggested that variation in the MTP gene might modify human longevity. Because of its function in lipid metabolism, the MTP gene product could plausibly play a pivotal role in the physiology of aging. However, the association observed in the U.S. samples could not be replicated by the same authors in a larger French LLI sample. We have therefore investigated the MTP "risk" haplotype in our own collection of 1,589 German nonagenarians, centenarians, and appropriately matched controls. No statistically significant differences were observed between LLI and controls at the allele, genotype, or haplotype level. This indicates that a noteworthy influence of the respective MTP haplotype on human longevity in the German population is unlikely. Furthermore, in comparison with all other U.S. and European samples analyzed, the MTP "risk" haplotype was found to be overrepresented only in the U.S. controls. This implies that the putative association is more likely to reflect recent changes in the genetic structure of the U.S. Caucasian population as a whole, rather than genetic effects upon survival to old age. In our view, the original study therefore highlights potential problems that arise when the case-control design is used as a means to map longevity genes in humans.