Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or "wet" form of AMD, no ...therapy is successful for the non-neovascular or "dry" form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.
Background We report a genome-wide association study (GWAS) of two populations, African-American and European-American (AA, EA) for opioid dependence (OD) in three sets of subjects, to identify ...pathways, genes, and alleles important in OD risk. Methods The design employed three phases (on the basis of separate sample collections). Phase 1 included our discovery GWAS dataset consisting of 5697 subjects (58% AA) diagnosed with opioid and/or other substance dependence and control subjects. Subjects were genotyped with the Illumina OmniQuad microarray, yielding 890,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Additional genotypes were imputed with the 1000 Genomes reference panel. Top-ranked findings were further evaluated in Phase 2 by incorporating information from the publicly available Study of Addiction: Genetics and Environment dataset, with GWAS data from 4063 subjects (32% AA). In Phase 3, the most significant SNPs from Phase 2 were genotyped in 2549 independent subjects (32% AA). Analyses were performed with case-control and ordinal trait designs. Results Most significant results emerged from the AA subgroup. Genome-wide-significant associations ( p < 5.0 × 10−8 ) were observed with SNPs from multiple loci– KCNG2* rs62103177 was most significant after combining results from datasets in every phase of the study. The most compelling results were obtained with genes involved in potassium signaling pathways (e.g., KCNC1 and KCNG2 ). Pathway analysis also implicated genes involved in calcium signaling and long-term potentiation. Conclusions This is the first study to identify risk variants for OD with GWAS. Our results strongly implicate risk pathways and provide insights into novel therapeutic and prevention strategies and might biologically bridge OD and other non–substance dependence psychiatric traits where similar pathways have been implicated.
Opioid dependence (OD) is at epidemic levels in the United States. Genetic studies can provide insight into its biology.
We completed an OD genome-wide association study in 3058 opioid-exposed ...European Americans, 1290 of whom met criteria for a DSM-IV diagnosis of OD. Analysis used DSM-IV criterion count.
By meta-analysis of four cohorts, Yale-Penn 1 (n = 1388), Yale-Penn 2 (n = 996), Yale-Penn 3 (n = 98), and SAGE (Study of Addiction: Genetics and Environment) (n = 576), we identified a variant on chromosome 15, rs12442183, near RGMA, associated with OD (p = 1.3 × 10−8). The association was also genome-wide significant in Yale-Penn 1 taken individually and nominally significant in two of the other three samples. The finding was further supported in a meta-analysis of all available opioid-exposed African Americans (n = 2014 1106 meeting DSM-IV OD criteria; p = 3.0 × 10−3) from three cohorts; there was nominal significance in two of these samples. Thus, of seven subsamples examined in two populations, one was genome-wide significant, and four of six were nominally (or nearly) significant. RGMA encodes repulsive guidance molecule A, which is a central nervous system axon guidance protein. Risk allele rs12442183*T was correlated with higher expression of a specific RGMA transcript variant in frontal cortex (p = 2 × 10−3). After chronic morphine injection, the homologous mouse gene (Rgma) was upregulated in C57BL/6J striatum. Coexpression analysis of 1301 brain samples revealed that RGMA messenger RNA expression was associated with that of four genes implicated in other psychiatric disorders, including GRIN1.
This is the first study to demonstrate an association of RGMA with OD. It provides a new lead into our understanding of OD pathophysiology.
Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute ...substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated.
To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics.
This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment SAGE, and International Consortium on the Genetics of Heroin Dependence ICGHD). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015.
Criterion count for DSM-IV CAD.
Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54, P = 4.32 × 10-10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54, P = 1.33 × 10-9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); and rs77378271 (β = 0.29, P = 2.13 × 10-8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development.
These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.
Background Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate ...gene association studies have identified few genetic variants that contribute to PTSD risk. Methods We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Results In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance ( p = 3.97×10−8 ). A SNP that maps to the first intron of the Tolloid-Like 1 gene ( TLL1 ) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1 , rs6812849 and rs7691872, with p values of 6.3×10−6 and 2.3×10−4 , respectively. In the combined sample, rs6812849 had a p value of 3.1×10−9 . No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results. Conclusions This study identified TLL1 as a new susceptibility gene for PTSD.
Age-related macular degeneration (AMD) is a common, late-onset, and complex trait with multiple risk factors. Concentrating on a region harboring a locus for AMD on 1q25-31, the ARMD1 locus, we ...tested single-nucleotide polymorphisms for association with AMD in two independent case-control populations. Significant association (P = 4.95 x 10⁻¹⁰) was identified within the regulation of complement activation locus and was centered over a tyrosine-402 rightwards arrow histidine-402 protein polymorphism in the gene encoding complement factor H. Possession of at least one histidine at amino acid position 402 increased the risk of AMD 2.7-fold and may account for 50% of the attributable risk of AMD.
Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) ...domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease.
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•Intermolecular β sheet hydrogen bonding and cation-π interactions drive FUS demixing•Cation-π interactions form between C-terminal arginines and N-terminal tyrosines•Cation-π strength is regulated by arginine methylation and interacting proteins•FUS hypomethylation in FTLD induces FUS gelation and impairs RNP granule function
Phase transition of the RNA-binding protein FUS is mediated by cation-π interactions between C-terminal arginines and N-terminal tyrosines and is modulated by arginine methlylation.
Improving accuracy in genetic studies would greatly accelerate understanding the genetic basis of complex diseases. One approach to achieve such an improvement for risk variants identified by the ...genome wide association study (GWAS) approach is to incorporate previously known biology when screening variants across the genome. We developed a simple approach for improving the prioritization of candidate disease genes that incorporates a network diffusion of scores from known disease genes using a protein network and a novel integration with GWAS risk scores, and tested this approach on a large Alzheimer disease (AD) GWAS dataset. Using a statistical bootstrap approach, we cross-validated the method and for the first time showed that a network approach improves the expected replication rates in GWAS studies. Several novel AD genes were predicted including CR2, SHARPIN, and PTPN2. Our re-prioritized results are enriched for established known AD-associated biological pathways including inflammation, immune response, and metabolism, whereas standard non-prioritized results were not. Our findings support a strategy of considering network information when investigating genetic risk factors.
With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD).
To detect genetic risk variants for OUD and determine genetic ...correlations and causal association with OUD and other traits.
A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations.
Main outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment).
A total of 114 759 individuals (101 016 men 88%; mean SD age, 60.1 12.8 years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 SE = 0.012; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis.
This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci.
...we should expect that large-scale next-generation sequencing studies including the US National Institutes of Health-sponsored Alzheimer's Disease Sequencing Project will not only identify rare ...functional disease-related single nucleotide changes and small insertions or deletions, but also larger structural variants, including some that are common in several populations.
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