👤 Karl-Josef Franke

Prior research on the genetics of human longevity has identified only a few robust associations. While these studies highlight the importance of metabolic processes for longevity, the contribution of immune genes, specifically those in the highly polymorphic human leukocyte antigen (HLA) region, remains understudied. Here, we addressed this gap by analysing the influence of HLA variation on longevity in Europeans. We conducted an initial case-control study, comparing imputed HLA alleles from a German longevity cohort with younger controls. Associations were evaluated with logistic regression, adjusting for multiple testing and population structure. Subsequently, significant associations (adjusted P ≤ 0.05) were tested for replication in two additional populations of similar ancestry: a Danish longevity cohort and the UK Biobank. Furthermore, epitope binding and immunogenicity predictions were performed to detect potential mechanisms linking HLA alleles to longevity. Our analysis revealed a novel male-specific association of HLA-DRB1*15:01:01 with longevity (adjusted P = 2.80 × 10 The novel male-specific association between HLA-DRB1*15:01 and longevity has been observed in three independent cohorts. The anti-longevity effect of this association is perhaps a consequence of an increase in Alzheimer's disease (AD)-related mortality in men carrying this allele. This hypothesis is based on prior research that has identified a male-specific association between HLA-DRB1*15:01:01 and AD. Additionally, it is likely that this link is mediated by increased immune reactivity against APOB-100, which is promoted by HLA-DRB1*15:01:01. Show less

OxPL-apoB (oxidized phospholipids [OxPL] on apoB-100), which include OxPL present on Lp(a) (lipoprotein[a]), are associated with higher cardiovascular risk. Experimental studies suggest that OxPL may influence platelet function. This observational study assessed the association of OxPL-apoB with intrinsic and on‑clopidogrel platelet reactivity and long-term cardiovascular events in patients undergoing coronary angiography with or without percutaneous coronary intervention in 2040 patients in the EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate). The association of OxPL-apoB to expression of CD62P, CD41, or PAC-1 levels and intrinsic and on-clopidogrel platelet reactivity to collagen and ADP was determined. The relationship of OxPL-apoB and Lp(a) to myocardial infarction-free survival and all-cause mortality at a median of 7 years was assessed using Cox regression models. Elevated levels of OxPL-apoB were associated with the severity of coronary obstruction, and higher prevalence of prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass graft surgery. No significant associations were present between OxPL-apoB and intrinsic or on-clopidogrel platelet reactivity or activation of platelet receptors. Analyzed individually in separate multivariable models, both OxPL-apoB (hazard ratio, 1.022 [95% CI, 1.005-1.040]; In patients undergoing coronary angiography with or without percutaneous coronary intervention, OxPL-apoB was not associated with intrinsic and on-clopidogrel platelet reactivity mediated by collagen or ADP. The association of OxPL-apoB and Lp(a) suggests that the accumulation of OxPL on Lp(a) may be a key determinant of long-term cardiovascular outcomes. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00457236. Show less

Premature myocardial infarction (MI) risk factors, including genetic ones, are crucial for an individual risk stratification. The aim of this study was to investigate the role of genetic variants in young patients with MI and a family history of premature atherosclerosis (FHpa). The studied group consisted of 70 patients aged 26-49 (mean 43.1, SD ± 4.3; 17 women, 53 men), with MI and with FHpa. The targeted enrichment library was prepared and analyzed using the Next-Generation Sequencing method. The results of sequencing were compared to data from the reference control population, consisting of 597 people with no history of MI (418 women, 179 men) aged 18-83 (mean 40.5, SD ± 12.4), using Propensity Score Matching. Show less

The pleiotropic cytokine IL-6 regulates numerous processes in the body, including neuronal functions. IL-6 either binds to membrane-bound receptor (mIL-6R) and triggers signaling via heteromerization with the signal transducer gp130 (classical signaling), or binds to its soluble form (sIL-6R) to act on cells that do not express mIL-6R (trans-signaling). The ß-secretase BACE1 can cleave gp130 as well as IL-6R and we hypothesized that BACE1 may alter neuron activity and synaptic transmission via modulation of IL-6 signaling. We used multielectrode array (MEA) recordings to monitor electrical activity of neuronal networks in acute cerebellar slices as well as long-term potentiation (LTP) induced by high-frequency stimulation in the hippocampus and to assess how exposure to IL-6 affects these processes. A pharmacological approach was applied to elucidate the contribution of trans-signaling involving BACE1. Spontaneous neuronal activity in cerebellar slices significantly decreased upon perfusion with IL-6 but not LIF and recovered during wash out. BACE1 inhibitors verubecestat or AZD3839 abolished the inhibitory effects of IL-6. Furthermore, IL-6 and LIF reversibly inhibited LTP in hippocampal slices, and in contrast to cerebellar neurons, BACE1 inhibitors verubecestat or AZD3839 did not abolish the inhibitory effect of IL-6 on LTP. Interestingly, a dramatic rebound effect on excitatory postsynaptic potentials was observed with BACE1 inhibitor AZD3839 but not verubecestat during wash out. Our results support relevant and differential roles of IL-6, LIF and BACE1 in pathways modulating neuronal discharge activity in the cerebellum and the synaptic plasticity in the hippocampus, and a possible involvement of this interaction in deficits of memory and learning. Show less

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. However, the genetic basis linking sociability with DMN function remains underexplored. This study aimed to elucidate the shared genetics and causal relationship between sociability and DMN-related resting-state functional MRI (rs-fMRI) traits. We conducted a comprehensive genomic analysis using large-scale genome-wide association study (GWAS) summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits ( Significant local genetic correlations were identified between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the cingulate and angular/temporal cortices. MR analyses suggested potential causal effects of sociability on 12 rs-fMRI traits. Seventeen genes were highly prioritized, with By combining genomic and transcriptomic data, our gene prioritization strategy may serve as a blueprint for future studies. Our findings can guide further research into the biological mechanisms underlying sociability and its role in the development, prognosis, and treatment of neuropsychiatric disorders. Show less

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, with Show less

Endoscopic lung volume reduction (ELVR) with one-way valves produces beneficial outcomes in patients with severe emphysema. Evidence on the efficacy remains unclear in patients with a very low forced expiratory volume in 1 s (FEV All data originated from the German Lung Emphysema Registry (Lungenemphysem Register), which is a prospective multicentric observational study for patients with severe emphysema after lung volume reduction. Two groups were formed at baseline: FEV 33 patients with FEV Our study highlights the potential efficacy of one-way valves, even in patients with very low FEV Show less

DNA methylation (DNAm) is an epigenetic mark with essential roles in disease development and predisposition. Here, we created genome-wide maps of methylation quantitative trait loci (meQTL) in three peripheral tissues and used Mendelian randomization (MR) analyses to assess the potential causal relationships between DNAm and risk for two common neurodegenerative disorders, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Genome-wide single nucleotide polymorphism (SNP; ~5.5M sites) and DNAm (~850K CpG sites) data were generated from whole blood (n=1,058), buccal (n=1,527) and saliva (n=837) specimens. We identified between 11 and 15 million genome-wide significant (p<10 Show less

To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis. We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes. We identified 2 independent risk loci harboring genome-wide significant variants ( This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism. Show less

Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society. Show less

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less

Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82315) and GWAS data on 7 subcortical brain volumes and ICV (n = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICV (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent. Show less

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. Show less

Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents. Show less

Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is known about its genetic architecture or its broader phenotype, non-LS sarcoidosis. To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS. An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects. A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated. Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region. Show less

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. Show less

The functional mechanisms underlying disease association remain unknown for Genome-wide Association Studies (GWAS) susceptibility variants located outside coding regions. Synthesis of effects from multiple surrounding functional variants has been suggested as an explanation of hard-to-interpret findings. We define filter criteria based on linkage disequilibrium measures and allele frequencies which reflect expected properties of synthesizing variant sets. For eligible candidate sets, we search for haplotype markers that are highly correlated with associated variants. Via simulations we assess the performance of our approach and suggest parameter settings which guarantee 95% sensitivity at 20-fold reduced computational cost. We apply our method to 1000 Genomes data and confirmed Crohn's Disease (CD) and Type 2 Diabetes (T2D) variants. A proportion of 36.9% allowed explanation by three-variant-haplotypes carrying at least two functional variants, as compared to 16.4% for random variants ([Formula: see text]). Association could be explained by missense variants for MUC19, PER3 (CD) and HMG20A (T2D). In a CD GWAS-imputed using haplotype reference consortium data (64 976 haplotypes)-we could confirm the syntheses of MUC19 and PER3 and identified synthesis by missense variants for 6 further genes (ZGPAZ, GPR65, CLN3/NPIPB8, LOC102723878, rs2872507, GCKR). In all instances, the odds ratios of the synthesizing haplotypes were virtually identical to that of the index SNP. In summary, we demonstrate the potential of synthesis analysis to guide functional follow-up of GWAS findings. All methods are implemented in the C/C ++ toolkit GetSynth, available at http://sourceforge.net/projects/getsynth/ tim.becker@uni-greifswald.de Supplementary data are available at Bioinformatics online. Show less

The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up. Show less

Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. Show less

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57)). After a correction for multiple comparisons (P-value<2.2×10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits. Show less

Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity. Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q). Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs. Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary. Show less

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. Show less

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney. Show less

Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies. Show less

Deletions within the neurexin 1 gene (NRXN1; 2p16.3) are associated with autism and have also been reported in two families with schizophrenia. We examined NRXN1, and the closely related NRXN2 and NRXN3 genes, for copy number variants (CNVs) in 2977 schizophrenia patients and 33 746 controls from seven European populations (Iceland, Finland, Norway, Germany, The Netherlands, Italy and UK) using microarray data. We found 66 deletions and 5 duplications in NRXN1, including a de novo deletion: 12 deletions and 2 duplications occurred in schizophrenia cases (0.47%) compared to 49 and 3 (0.15%) in controls. There was no common breakpoint and the CNVs varied from 18 to 420 kb. No CNVs were found in NRXN2 or NRXN3. We performed a Cochran-Mantel-Haenszel exact test to estimate association between all CNVs and schizophrenia (P = 0.13; OR = 1.73; 95% CI 0.81-3.50). Because the penetrance of NRXN1 CNVs may vary according to the level of functional impact on the gene, we next restricted the association analysis to CNVs that disrupt exons (0.24% of cases and 0.015% of controls). These were significantly associated with a high odds ratio (P = 0.0027; OR 8.97, 95% CI 1.8-51.9). We conclude that NRXN1 deletions affecting exons confer risk of schizophrenia. Show less