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Persistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10 -8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.

To compare the association of smoking with age-related macular degeneration (AMD) in the Muenster Aging and Retina Study (MARS) cohort with current evidence. Adjusted risk ratios for incident AMD in MARS were compared with findings of a systematic review and meta-analysis of observational prospective studies. 9.6% of MARS participants progressed to AMD over a median of 30.9 months. In MARS the adjusted risk ratio in current versus never smokers was 3.25 (95% confidence interval [1.50-7.06]), and 1.28 [0.70-2.33] in former smokers versus never smokers. The meta-analysis of previous studies showed a pooled adjusted risk ratio of 2.51 [1.09-5.76] in current versus never smokers. Inclusion of the MARS findings removed between-study heterogeneity and accentuated the pooled adjusted risk ratio for current smokers to 2.75 [1.52-4.98]. Specific analyses in MARS revealed a protective effect for time since smoking cessation in former smokers with an adjusted risk ratio=0.50 [0.29-0.89] per log(year). Current smoking nearly triples AMD incidence, while smoking cessation lowers AMD incidence in a non-linear fashion even in the elderly.

Purpose Smoking is an established risk factor for the development of age-related maculopathy (ARM), and its end stage, age-related macular degeneration (AMD). We evaluated the benefit of various smoking-related variables in modeling the association of smoking with ARM and AMD in a mixed sample of current, former, and never smokers. Methods This was a cross-sectional study in participants of the Muensteraner Altern- und Retina-Studie (MARS). Participants were classified according to the Rotterdam classification system as healthy, or having ARM or AMD. Using multinomial logistic regression techniques, the association with number of cigarettes, years of smoking, pack-years and time since cessation in former smokers were evaluated. Results Mean age of the 982 participants (58.6% females) was 70.9 ± 5.5 years. ARM was present in 483 (49.2%) and AMD in 285 (29.0%) individuals. The adjusted prevalence odds ratio (OR) in current smokers versus never smokers was 2.61 (95% confidence interval [CI] 1.34–5.09) for ARM and 3.94 (95% CI 1.91–8.14) for AMD. This effect decreased in former smokers with an OR = 0.55 (95% CI 0.33–0.99) per log-transformed time since smoking cessation for ARM and an OR = 0.52 (95% CI 0.30–0.90) for AMD. Conclusions By including a variable for time since smoking cessation, we were able to handle current, former, and never smokers in one model that estimates the association of smoking with ARM or AMD. Logarithmical transformation of the time since smoking cessation seemed to increase the model fit and to reflect a non-linear protective effect of smoking cessation on the onset of ARM and AMD in former smokers.

The search for genes involved in the pathogenesis of stroke has been highlighted as a field of needs. We followed the concept, that stroke represents a complex genetic disorder, and analyzed the contribution of 106 informative single nucleotide polymorphisms (SNPs) from 63 candidate genes for cardiovascular diseases for the risk of stroke. We conducted two independent case-control studies in two different German regions and recruited a total of 1,901 hospitalized stroke cases and 1,747 regional population controls. The smaller of both studies was used as the replication study. Multiplex PCR in combination with allele-specific hybridization was used for genotype determination. Descriptive statistics, permutations and multivariable logistic regression were used in the analyses. After permutation testing 5 SNPs, located in the nitric oxide synthase 3, the alpha 2 integrin, the interleukin 13, the selectin P and the chemokine receptor 2 genes, had a significant allele difference between cases and controls in the larger study. For one of these SNPs, the glu298asp polymorphism in the nitric oxide synthase 3 gene, an association with ischemic stroke was replicated in the second study and also in a combined analysis of both studies. This association was independent of age, gender, hypertension, diabetes and hypercholesterolemia in both studies. Using large sample sizes and a replication study approach, we found evidence for a role of a polymorphism in the nitric oxide synthase 3 gene in stroke onset.

Barban N, Jansen R, de Vlaming R, Vaez A, Mandemakers JJ, Tropf FC, Shen X, Wilson JF, Chasman DI, Nolte IM, Tragante V, van der Laan SW, Perry JR, Kong A; BIOS Consortium, Ahluwalia TS, Albrecht E, Yerges-Armstrong L, Atzmon G, Auro K, Ayers K, Bakshi A, Ben-Avraham D, Berger K, Bergman A, Bertram L, Bielak LF, Bjornsdottir G, Bonder MJ, Broer L, Bui M, Barbieri C, Cavadino A, Chavarro JE, Turman C, Concas MP, Cordell HJ, Davies G, Eibich P, Eriksson N, Esko T, Eriksson J, Falahi F, Felix JF, Fontana MA, Franke L, Gandin I, Gaskins AJ, Gieger C, Gunderson EP, Guo X, Hayward C, He C, Hofer E, Huang H, Joshi PK, Kanoni S, Karlsson R, Kiechl S, Kifley A, Kluttig A, Kraft P, Lagou V, Lecoeur C, Lahti J, Li-Gao R, Lind PA, Liu T, Makalic E, Mamasoula C, Matteson L, Mbarek H, McArdle PF, McMahon G, Meddens SF, Mihailov E, Miller M, Missmer SA, Monnereau C, van der Most PJ, Myhre R, Nalls MA, Nutile T, Kalafati IP, Porcu E, Prokopenko I, Rajan KB, Rich-Edwards J, Rietveld CA, Robino A, Rose LM, Rueedi R, Ryan KA, Saba Y, Schmidt D, Smith JA, Stolk L, Streeten E, Tönjes A, Thorleifsson G, Ulivi S, Wedenoja J, Wellmann J, Willeit P, Yao J, Yengo L, Zhao JH, Zhao W, Zhernakova DV, Amin N, Andrews H, Balkau B, Barzilai N, Bergmann S, Biino G, Bisgaard H, Bønnelykke K, Boomsma DI, Buring JE, Campbell H, Cappellani S, Ciullo M, Cox SR, Cucca F, Toniolo D, Davey-Smith G, Deary IJ, Dedoussis G, Deloukas P, van Duijn CM, de Geus EJ, Eriksson JG, Evans DA, Faul JD, Sala CF, Froguel P, Gasparini P, Girotto G, Grabe HJ, Greiser KH, Groenen PJ, de Haan HG, Haerting J, Harris TB, Heath AC, Heikkilä K, Hofman A, Homuth G, Holliday EG, Hopper J, Hyppönen E, Jacobsson B, Jaddoe VW, Johannesson M, Jugessur A, Kähönen M, Kajantie E, Kardia SL, Keavney B, Kolcic I, Koponen P, Kovacs P, Kronenberg F, Kutalik Z, La Bianca M, Lachance G, Iacono WG, Lai S, Lehtimäki T, Liewald DC; LifeLines Cohort Study, Lindgren CM, Liu Y, Luben R, Lucht M, Luoto R, Magnus P, Magnusson PK, Martin NG, McGue M, McQuillan R, Medland SE, Meisinger C, Mellström D, Metspalu A, Traglia M, Milani L, Mitchell P, Montgomery GW, Mook-Kanamori D, de Mutsert R, Nohr EA, Ohlsson C, Olsen J, Ong KK, Paternoster L, Pattie A, Penninx BW, Perola M, Peyser PA, Pirastu M, Polasek O, Power C, Kaprio J, Raffel LJ, Räikkönen K, Raitakari O, Ridker PM, Ring SM, Roll K, Rudan I, Ruggiero D, Rujescu D, Salomaa V, Schlessinger D, Schmidt H, Schmidt R, Schupf N, Smit J, Sorice R, Spector TD, Starr JM, Stöckl D, Strauch K, Stumvoll M, Swertz MA, Thorsteinsdottir U, Thurik AR, Timpson NJ, Tung JY, Uitterlinden AG, Vaccargiu S, Viikari J, Vitart V, Völzke H, Vollenweider P, Vuckovic D, Waage J, Wagner GG, Wang JJ, Wareham NJ, Weir DR, Willemsen G, Willeit J, Wright AF, Zondervan KT, Stefansson K, Krueger RF, Lee JJ, Benjamin DJ, Cesarini D, Koellinger PD, den Hoed M, Snieder H, Mills MC.

Recent guidelines on acute myocardial infarction (AMI) are based on randomized clinical trials (RCTs) and registries with selected patients, and may therefore not represent 'real-life'. This analysis shows for the first time nationwide trends in AMI from Germany.We were provided with data on all in-patient hospitalizations by the Federal Statistical Office. All hospitalized cases with AMI (onset of symptoms28 days) from the years 2005, 2007, and 2009 were analysed regarding morbidity, in-hospital mortality, treatments, and costs. Analysis of a total of 16.1, 16.6, and 17.2 million hospitalizations showed the proportion of coded AMI to remain relatively constant (1276, 1272, and 1181 per 100 000 hospitalizations in 2005, 2007, and 2009). The proportion of ST-elevation AMI decreased over time (STEMI; 631, 546, and 454 per 100 000 hospitalizations),while non-ST-elevation AMI increased (NSTEMI; 645, 726, and 727 per 100 000 hospitalizations). The proportion of older patients75 years (+4.6%), of comorbidities such as hypertension (+5.8%), diabetes (+17.7%), left ventricular failure (+19.8%), peripheral artery disease (+13.3%), and chronic kidney disease (+165.4%) increased as well. In-hospital mortality remained relatively stable during this period in AMI cases overall (11.1, 10.7, 10.8%) but changed slightly in STEMI (11.2, 11.9, 12.2%) and NSTEMI (11.0, 9.9, 9.9%). Causing about 1.2% of hospitalizations, AMI accounted for 2.5% (1.2 billion €) of in-hospital health expenses.This hospitalization-based analysis revealed a marked increase of NSTEMI among constant AMI frequency. Despite all current efforts, in-hospital mortality was stagnating on a high level compared with data of RCTs.

To prospectively evaluate the impact of homozygosity in the A69S-SNP of the LOC387715-gene, smoking history, and their interaction on visual functional status (v-FS) in age-related macular degeneration (AMD).The Muenster Aging and Retina Study (MARS) cohort (n = 656; 58.8% women, mean age 70.2 years) was followed over a mean of 2.5 years. AMD-status, genotype and smoking history were assessed at baseline. V-FS [from 0 (low) to 100 (unimpaired) points in general-, near- and far-vision], were AMD-status assessed at baseline and at follow-up. Linear models with stepwise adjustments for covariates were used to analyze decline of v-FS over time.In initial models, homozygosity for the A69S-variant was negatively associated with all three dimensions of the v-FS. After including smoking history, ever smoking was negatively associated with declines in near and far vision (-4.82 and -5.12 points, respectively; each p0.05). In smokers homozygous for the A69S-variant the number of cigarettes smoked per day (smoking intensity) was negatively associated with all three dimensions of the v-FS (interaction term each p0.05). Time since smoking cessation in former smokers protected against declines in near and far vision. These effects were independent of the AMD-status at baseline.The interaction of homozygosity for the A69S-variant and smoking intensity had a negative impact on general-, near-, and far visual functional status independent of AMD-status. Quitting smoking seemed to have a time-dependent protective effect on near and far vision.

Objective To evaluate recent reports indicating that plasma levels of fibrinogen and high-sensitivity C-reactive protein (CRP) are associated with age-related maculopathy (ARM). Methods From the baseline examinations of the Muenster Aging and Retina Study, a cohort of 1060 subjects aged 59 to 82 years was assembled. Of these, 873 persons (82%) with bilateral gradable fundus photographs and complete data on fibrinogen, CRP, and potential confounders were included in a cross-sectional analysis. The main outcome measure was the association among fibrinogen, CRP, and ARM as assessed by multivariate logistic regression analysis. Results Fibrinogen and CRP levels were higher among participants with early and late ARM than among those without ARM. The crude odds ratios for ARM between the highest vs the lowest quartile were 1.90 (95% confidence interval [CI], 1.29-2.80) for fibrinogen and 1.43 (95% CI, 0.97-2.10) for CRP. After adjustment for cardiovascular risk factors, these odds ratios were 1.37 for fibrinogen (95% CI, 0.91-2.06) and 1.12 (95% CI, 0.73-1.73) for CRP. Conclusions After adjustment for cardiovascular risk factors, we found no statistically significant association between fibrogen, CRP, and ARM. Therefore, our results do not indicate a role of systemic inflammation in ARM beyond what is already present owing to concurrent cardiovascular disease.

It has been hypothesized that the macular carotenoids, lutein and zeaxanthin, may protect against age-related maculopathy. We evaluated the association between blood concentrations of lutein (L) and zeaxanthin (Z) and age-related maculopathy (ARM) in a case-control analysis of the baseline examination of the Muenster Ageing and Retina Study (MARS).Of the 1060 participants aged 59-82 years at baseline, 910 (85.9%) with bilateral gradable fundus photographs and complete data for the carotenoids and potential confounders were included. The Rotterdam classification system was used for definition of ARM stages. Multivariate linear regression methods were applied to model the relationship between macular carotenoids and the presence of ARM.The participants' mean age was 70.9+5.5 years, 59.9% were female, 20.8% had a normal bilateral fundus, and 48.5% showed signs of early ARM (uni- or bilateral) and 30.7% of late ARM (in at least one eye). In study participants with L and/or Z supplementation (15.6%), the median serum levels for L (Z) were approximately 2 times (1.5 times) higher than in subjects with no supplementation. After exclusion of subjects with L and/or Z supplementation, no statistically significant bivariate relationship was observed between the serum levels of L or Z and the presence of ARM. Multivariate regression models, adjusting for age, gender, smoking, body-mass index, and HDL-cholesterol blood levels, produced adjusted mean serum levels of 0.124, 0.112, and 0.131 microg/ml for L and 0.019, 0.020, and 0.022 microg/ml for Z in subjects with normal fundus, early ARM, and late ARM, respectively.In this large study, the serum concentrations of L and Z were not related to the prevalence of ARM. However, the large proportion of study participants taking L and/or Z supplementation may have affected these results.