Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple ...strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
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•Almost 20% of MS risk heritability can be attributed to common genetic variants•We show that nearly 5% of heritability is explained by coding low-frequency variants•We identify four novel genes driving risk independently of common-variant signals•These genes would not have been found by common-variant studies
In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology.
IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases ...and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.
Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex ...differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.
We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.
Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).
In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these ...machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52-79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intraindividual differences. This will create substantial challenges in humans, where multiple tissues are not readily available.
Objective
Febrile seizure is a common childhood disorder that affects 2–5% of all children, and is associated with later development of epilepsy and psychiatric disorders. This study determines how ...the incidence of febrile seizures correlates with birth characteristics, age, sex and brain development.
Methods
This is a cohort study of all children born Denmark between 1977 and 2011 who were alive at 3 months of age (N = 2,103,232). The Danish National Patient Register was used to identify children with febrile seizures up to 5 years of age. Follow‐up ended on 31 December 2016 when all cohort members had potentially reached 5 years of age.
Results
In total, 75,593 (3.59%, 95% CI: 3.57–3.62%) were diagnosed with febrile seizures. Incidence peaked at 16.7 months of age (median: 16.7 months, interquartile range: 12.5–24.0). The 5‐year cumulative incidence of febrile seizures increased with decreasing birth weight (<1500 g; 5.42% (95% CI: 4.98–5.88% vs. 3,000–4,000 g; 3.53% (95% CI: 3.50–3.56%)) and with decreasing gestational age at birth (31–32 weeks; 5.90% (95% CI: 5.40–6.44%) vs. 39–40 weeks; 3.56% (95% CI: 3.53–3.60)). Lower gestational age at birth was associated with higher age at onset of a first febrile seizure; an association that essentially disappeared when correcting for age from conception.
Conclusions
The risk of febrile seizures increased with decreasing birth weight and gestational age at birth. The association between low gestational age at birth and age at first febrile seizure suggests that onset of febrile seizures is associated with the stage of brain development.
Highlights ► Genetic risk variants often predispose to multiple autoimmune diseases. ► This can be used to infer shared and distinct pathogenic pathways. ► We propose several architectures for how ...such pathways are shared. ► This may lead to a mechanistic rather than symptomatic patient classification.
Abstract It has been more than 30 years since the initial trials of Cyclosporin A to treat patients with new onset Type 1 diabetes (T1D). Since that time, there have been insights into genetic ...predisposition to the disease, the failures of immune tolerance, and mechanisms that cause the immune mediated β cell destruction. The genetic loci associated affect lymphocyte development and tolerance mechanisms. Discoveries related to the roles of specific immune responses gene such as the major histocompatibility complex, PTPN22, CTLA-4, IL-2RA, as well as the mechanisms of antigen presentation in the thymus have suggested ways in which autoreactivity may follow changes in the functions of these genes that are associated with risk. Antigens that are recognized by the immune system in patients with T1D have been identified. With this information, insights into the novel cellular mechanisms leading to the initiation and orchestration of β cell killing have been developed such as the presentation of unique antigens within the islets. Clinical trials have been performed, some of which have shown efficacy in improving β cell function but none have been able to permanently prevent loss of insulin secretion. The reasons for the lack of long term success are not clear but may include the heterogeneity of the immune response and in individual responses to immune therapies, recurrence of autoimmunity after the initial effects of the therapies, or even intrinsic mechanisms of β cell death that proceeds independently of immune attack after initiation of the disease. In this review, we cover developments that have led to new therapeutics and characteristics of patients who may show the most benefits from therapies. We also identify areas of incomplete understanding that might be addressed to develop more effective therapeutic strategies.
Polygenic scores are increasingly powerful predictors of educational achievement. It is unclear, however, how sets of polygenic scores, which partly capture environmental effects, perform jointly ...with sets of environmental measures, which are themselves heritable, in prediction models of educational achievement. Here, for the first time, we systematically investigate gene-environment correlation (rGE) and interaction (GxE) in the joint analysis of multiple genome-wide polygenic scores (GPS) and multiple environmental measures as they predict tested educational achievement (EA). We predict EA in a representative sample of 7,026 16-year-olds, with 20 GPS for psychiatric, cognitive and anthropometric traits, and 13 environments (including life events, home environment, and SES) measured earlier in life. Environmental and GPS predictors were modelled, separately and jointly, in penalized regression models with out-of-sample comparisons of prediction accuracy, considering the implications that their interplay had on model performance. Jointly modelling multiple GPS and environmental factors significantly improved prediction of EA, with cognitive-related GPS adding unique independent information beyond SES, home environment and life events. We found evidence for rGE underlying variation in EA (rGE = .38; 95% CIs = .30, .45). We estimated that 40% (95% CIs = 31%, 50%) of the polygenic scores effects on EA were mediated by environmental effects, and in turn that 18% (95% CIs = 12%, 25%) of environmental effects were accounted for by the polygenic model, indicating genetic confounding. Lastly, we did not find evidence that GxE effects significantly contributed to multivariable prediction. Our multivariable polygenic and environmental prediction model suggests widespread rGE and unsystematic GxE contributions to EA in adolescence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison ...to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, ∼150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10−3, GWA scan; P < 10−6, replication; P = 10−9, combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 × 10−6 in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents ...determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted.
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