Showing papers by "Jonathan L. Haines published in 2018"
TL;DR: A meta-analysis of 139,555 Europeans identifies 68 new genomic loci associated with intraocular pressure, 68 of which are novel, which suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP.
Abstract: Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
191 citations
TL;DR: Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApOE rather than non-genetic ethnic, cultural, and environmental factors.
Abstract: The ApoE e4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by e4, however, differs across populations, with populations of African ancestry showing lower e4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE e4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE e4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene e4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.
120 citations
TL;DR: This work identifies 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.
112 citations
Tohoku University1, University of Tokyo2, Nagoya University3, Kyoto University4, University of Yamanashi5, University of Miyazaki6, Gifu University7, Hiroshima University8, Kobe University9, Kyushu University10, Iwate Medical University11, National University of Singapore12, Genome Institute of Singapore13, Case Western Reserve University14, Brigham and Women's Hospital15, Harvard University16, Menzies Research Institute17, Flinders University18, QIMR Berghofer Medical Research Institute19, University of Melbourne20, University of Western Australia21, Duke University22, University of Ibadan23, University of North Carolina at Chapel Hill24, University of Ghana25, University of the Witwatersrand26
TL;DR: The results improve the understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
Abstract: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.
103 citations
Adriana I Iglesias1, Aniket Mishra2, Veronique Vitart3, Yelena Bykhovskaya4 +153 more•Institutions (54)
TL;DR: The authors identify 19 novel genetic loci associated with CCT, a subset of which is involved in rare corneal or connective tissue disorders, and implicate candidate genes acting in collagen and extracellular matrix regulation.
Abstract: Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.
58 citations
QIMR Berghofer Medical Research Institute1, University of Tasmania2, Case Western Reserve University3, Harvard University4, Flinders University5, University of Adelaide6, Macquarie University7, University of Sydney8, University of Melbourne9, University of Auckland10, University of Otago11, University of Queensland12, University of Western Australia13, Duke University14, Marshfield Clinic15, University of North Carolina at Chapel Hill16, University of Iowa17, University of California, San Diego18, Wills Eye Institute19, University of Miami20, University of Michigan21, Georgia Regents University22, West Virginia University23, New York Eye and Ear Infirmary24, University of Pittsburgh25, Stanford University26, Mayo Clinic27, Johns Hopkins University28
TL;DR: This study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining geneticData from genetically-correlated eye traits for the purpose of gene discovery and mapping.
Abstract: Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - "response to fluid shear stress" and "abnormal retina morphology" - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.
33 citations
TL;DR: Multiple long-chain acylcarnitines that are part of the carnitine shuttle pathway were significantly increased in NV AMD patients compared to controls, suggesting that fatty acid metabolism may be involved in NVAMD pathophysiology.
Abstract: Purpose To identify metabolites and metabolic pathways altered in neovascular age-related macular degeneration (NVAMD). Methods We performed metabolomics analysis using high-resolution C18 liquid chromatography-mass spectrometry on plasma samples from 100 NVAMD patients and 192 controls. Data for mass/charge ratio ranging from 85 to 850 were captured, and metabolic features were extracted using xMSanalyzer. Nested feature selection was used to identify metabolites that discriminated between NVAMD patients and controls. Pathway analysis was performed with Mummichog 2.0. Hierarchical clustering was used to examine the relationship between the discriminating metabolites and NVAMD patients and controls. Results Of the 10,917 metabolic features analyzed, a set of 159 was identified that distinguished NVAMD patients from controls (area under the curve of 0.83). Of these features, 39 were annotated with confidence and included multiple carnitine metabolites. Pathway analysis revealed that the carnitine shuttle pathway was significantly altered in NVAMD patients (P = 0.0001). Tandem mass spectrometry confirmed the molecular identity of five carnitine shuttle pathway acylcarnitine intermediates that were increased in NVAMD patients. Hierarchical cluster analysis revealed that 51% of the NVAMD patients had similar metabolic profiles, whereas the remaining 49% displayed greater variability in their metabolic profiles. Conclusions Multiple long-chain acylcarnitines that are part of the carnitine shuttle pathway were significantly increased in NVAMD patients compared to controls, suggesting that fatty acid metabolism may be involved in NVAMD pathophysiology. Cluster analysis suggested that clinically indistinguishable NVAMD patients can be separated into distinct subgroups based on metabolic profiles.
33 citations
TL;DR: A significant portion of the genetic etiology of AD remains unknown and must be identified, and new insights are led to the potential role of microglia cells in addition to neuronal cells in the brain.
Abstract: Alzheimer disease (AD) is a huge and growing societal problem with upwards of 35% of the population over the age of 80 developing the disease. AD results in a loss of memory, the ability to make reasoned and sound decisions, and ultimately the inability to take care of oneself. AD has an impact not only on the sufferer, but their caretakers and loved ones, who must take on a costly and time-consuming burden of care. AD is found in virtually all racial and ethnic groups. Genetic influences on AD are substantial, and there has been a 30 year history of both success and failure. Mutations for rare early onset forms of the disease have been identified, but this information has not yet led to an effective treatment. Multiple common genetic variations have also been identified, and have led to new insights into the potential role of microglia cells in addition to neuronal cells in the brain. Despite intensive efforts, a significant portion of the genetic etiology of AD remains unknown and must be identified.
30 citations
TL;DR: An annotation process motivated by the Alzheimer’s Disease Sequencing Project is outlined, the impact of including tissue-specific transcript sets and sources of gene regulatory information are illustrated and the potential impact of changing genomic builds on the annotation process is assessed.
Abstract: Motivation Annotation of genomic variants is an increasingly important and complex part of the analysis of sequence-based genomic analyses. Computational predictions of variant function are routinely incorporated into gene-based analyses of rare-variants, though to date most studies use limited information for assessing variant function that is often agnostic of the disease being studied. Results In this work, we outline an annotation process motivated by the Alzheimer's Disease Sequencing Project, illustrate the impact of including tissue-specific transcript sets and sources of gene regulatory information and assess the potential impact of changing genomic builds on the annotation process. While these factors only impact a small proportion of total variant annotations (∼5%), they influence the potential analysis of a large fraction of genes (∼25%). Availability and implementation Individual variant annotations are available via the NIAGADS GenomicsDB, at https://www.niagads.org/genomics/ tools-and-software/databases/genomics-database. Annotations are also available for bulk download at https://www.niagads.org/datasets. Annotation processing software is available at http://www.icompbio.net/resources/software-and-downloads/. Supplementary information Supplementary data are available at Bioinformatics online.
30 citations
University of Washington1, United States Department of Veterans Affairs2, Columbia University3, University of Miami4, Vanderbilt University Medical Center5, Case Western Reserve University6, Washington University in St. Louis7, Boston University8, Icahn School of Medicine at Mount Sinai9, University of Pennsylvania10, Baylor College of Medicine11, University of Texas at Austin12
TL;DR: Evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP is described and pathogenic variants within dementia genes were predominantly rare and conserved coding changes.
Abstract: Background/Aims: The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer’s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as “pathogenic” in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
26 citations
TL;DR: The findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes and functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
Abstract: Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10−8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10−8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10−6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10−3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10−3) and visual (P = 5.6 × 10−4) cortices. Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
TL;DR: 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 is developed and tested on a large Alzheimer disease (AD) GWAS dataset and for the first time showed that a network approach improves the expected replication rates in GWAS studies.
Abstract: 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.
University of Liège1, University of Antwerp2, Lille University of Science and Technology3, University of Kentucky4, Erasmus University Medical Center5, Mayo Clinic6, Columbia University7, Boston University8, Case Western Reserve University9, John P. Hussman Institute for Human Genomics10, University of Pennsylvania11, Cardiff University12
TL;DR: A hypothesis-free sex-stratified genome-wide screening for epistasis contributing to Alzheimer's disease (AD) susceptibility points toward new AD-related pathways and provides clues toward novel medical targets for the cure of AD.
Yale University1, Brigham and Women's Hospital2, University of Miami3, University of Lübeck4, Katholieke Universiteit Leuven5, Johns Hopkins University School of Medicine6, University of Copenhagen7, Copenhagen University Hospital8, University of Helsinki9, French Alternative Energies and Atomic Energy Commission10, University of Nantes11, Max Planck Society12, Technische Universität München13, University of Mainz14, Augsburg College15, Charité16, Hochschule Hannover17, University Hospital Heidelberg18, University of Ulm19, Ruhr University Bochum20, University of Eastern Piedmont21, Vita-Salute San Raffaele University22, Medical Research Council23, University of Milan24, Erasmus University Rotterdam25, University of Oslo26, Haukeland University Hospital27, Oslo University Hospital28, Karolinska Institutet29, University of Zurich30, University of Cambridge31, Keele University32, King's College London33, University of Oxford34, University of California, San Francisco35, Washington University in St. Louis36, Vanderbilt University Medical Center37, Vertex Pharmaceuticals38, Northeastern University39, Children's Hospital of Philadelphia40, Wellesley College41, Kaiser Permanente42, Harvard University43, Menzies Research Institute44, Bond University45, University of Sydney46, University of California, Berkeley47, Columbia University Medical Center48
TL;DR: Four novel genes driving MS risk independently of common variant signals are identified, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis.
Abstract: Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 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, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. 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.
Case Western Reserve University1, QIMR Berghofer Medical Research Institute2, Brigham and Women's Hospital3, Massachusetts Eye and Ear Infirmary4, University of California, San Diego5, Harvard University6, Duke University7, University of Miami8, University of Michigan9, Marshfield Clinic10, New York University11, University of Iowa12, University of North Carolina at Chapel Hill13, West Virginia University14, Stanford University15, Mayo Clinic16, Wills Eye Institute17, New York Eye and Ear Infirmary18, Johns Hopkins University19, University of Illinois at Chicago20, Georgia Regents University21, Flinders University22, Menzies Research Institute23, University of Western Australia24
TL;DR: Assessing gene variants related to testosterone metabolism collectively and POAG risk found testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.
Abstract: Author(s): Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H; Butkiewicz, Mariusz; Sullivan, David A; Weinreb, Robert N; Aschard, Hugues; Allingham, R Rand; Ashley-Koch, Allison; Lee, Richard K; Moroi, Sayoko E; Brilliant, Murray H; Wollstein, Gadi; Schuman, Joel S; Fingert, John H; Budenz, Donald L; Realini, Tony; Gaasterland, Terry; Scott, William K; Singh, Kuldev; Sit, Arthur J; Igo, Robert P; Song, Yeunjoo E; Hark, Lisa; Ritch, Robert; Rhee, Douglas J; Vollrath, Douglas; Zack, Donald J; Medeiros, Felipe; Vajaranant, Thasarat S; Chasman, Daniel I; Christen, William G; Pericak-Vance, Margaret A; Liu, Yutao; Kraft, Peter; Richards, Julia E; Rosner, Bernard A; Hauser, Michael A; Craig, Jamie E; Burdon, Kathryn P; Hewitt, Alex W; Mackey, David A; Haines, Jonathan L; MacGregor, Stuart; Wiggs, Janey L; Pasquale, Louis R; Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) Consortium | Abstract: Purpose:Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk Methods:We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls) Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]) Results:In the US dataset, the SNP panel was not associated with POAG (permuted P = 077), although there was an association in the Australian sample (permuted P = 0018) In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0033) and not women (permuted P ≥ 042), but in gene-based analyses, there was no consistency on the main genes responsible for these findings In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0011), but again, gene-based analyses showed no consistent driver gene associations Conclusions:Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets
TL;DR: An ocular phenome-wide association study for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length indicates that in the South Indian families WNT6B SNP are primarily associated with CCT, and suggests that W NT7BSNPs can have population-specific effects on ocular quantitative traits.
Abstract: PURPOSE:
To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders.
METHODS:
One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN.
RESULTS:
Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval CI: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT.
CONCLUSIONS:
The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.
TL;DR: This study comprehensively re-sequenced the entire protein coding and noncoding portions of the gene and putative regulatory sequences in 82 ASD individuals and 55 developmentally typical pediatric controls, finding only a single common, coding variant, and no association of any single marker or set of variants with ASD.
Abstract: Alterations of the gamma-aminobutyric acid (GABA) signaling system has been strongly linked to the pathophysiology of autism spectrum disorder (ASD). Genetic associations of common variants in GABA receptor subunits, in particular GABRA4 on chromosome 4p12, with ASD have been replicated by several studies. Moreover, molecular investigations have identified altered transcriptional and translational levels of this gene and protein in brains of ASD individuals. Since the genotyped common variants are likely not the functional variants contributing to the molecular consequences or underlying ASD phenotype, this study aims to examine rare sequence variants in GABRA4, including those outside the protein coding regions of the gene. We comprehensively re-sequenced the entire protein coding and noncoding portions of the gene and putative regulatory sequences in 82 ASD individuals and 55 developmentally typical pediatric controls, all homozygous for the most significant previously associated ASD risk allele (G/G at rs1912960). We identified only a single common, coding variant, and no association of any single marker or set of variants with ASD. Functional annotation of noncoding variants identified several rare variants in putative regulatory sites. Finally, a rare variant unique to ASD cases, in an evolutionary conserved site of the 3′UTR, shows a trend toward decreasing gene expression. Hence, GABRA4 rare variants in noncoding DNA may be variants of modest physiological effects in ASD etiology.
TL;DR: The type of family sampled for a study will determine the statistical analyses and power of discovery of genetic findings, and study designs that maximize power and allow for linkage and association analyses to identify genetic loci predisposing to phenotype are evaluated.
Abstract: In this article, we discuss strategies for selection of families and family members for genetic studies. We will evaluate strategies to sample large families with multiply affected members, sibships, and nuclear families. In addition, we have added a section to discuss sub-sampling within pedigrees for large sequencing studies, particularly when genome-wide SNP chips are available on all members of a pedigree. The type of family sampled for a study will determine the statistical analyses and power of discovery of genetic findings. We will evaluate study designs that maximize power and allow for linkage and association analyses to identify genetic loci predisposing to phenotype. © 2018 by John Wiley & Sons, Inc.
TL;DR: Different genetic risk factors may be more relevant to the prediction of cognitive decline in individuals with high African ancestry compared to individuals with low African Ancestry and self-identified ‘non-Hispanic White’.
Abstract: ory were conducted in the group of self-identified ‘non-Hispanic White’. Results:The group with African ancestry showed a continuous distribution between 10% and 94% (Figure 1b). Linear mixed models revealed a significant three-way interaction between time, percent African ancestry, and APOE4 status (p1⁄40.003), such that the impact of APOE4 on memory decline was most pronounced at lower percentages of African ancestry. Post-hoc analyses dividing the sample based on a median split of African ancestry confirmed the direction of the interaction, showing a significant effect of APOE4 on memory decline only in the low African ancestry group (b1⁄4-0.18, p<0.001) but not for the high African ancestry group (b1⁄40.02, p1⁄40.6) (Figure 2). Conclusions:A greater percentage of African ancestry is associated with a reduced effect of APOE4 on memory decline. Thus, different genetic risk factors may be more relevant to the prediction of cognitive decline in individuals with high African ancestry compared to individuals with low African Ancestry and self-identified ‘non-Hispanic White’.
TL;DR: Amit Kawalia, Alfredo Ramirez, Wiesje M. Van der Flier, Philip Scheltens, Marcel JT.
Abstract: Amit Kawalia, Alfredo Ramirez, Wiesje M. Van der Flier, Philip Scheltens, Marcel JT. Reinders, Isabel Hernandez, Alberto Lle o, Juan Fortea, Najada Stringa, Agust ın Ruiz Ruiz, Ignacio Ill an-Gala, Estrella Morenas-Rodr ıguez, Jordi Clarimon, Carmen Lage, Erik van den Akker, Eloy Rodr ıguez Rodr ıguez, Pascual S anchez-Juan, Yolande A. L. Pijnenburg, Natasja van Schoor, Javier Simon-Sanchez, Afina W. Lemstra, Peter Heutink, Sonja Scholz, Martijn Huisman, Eline Slagboom, Henne Holstege and Alzheimer Disease European DNA Biobank, International Frontotemporal Dementia Genomics Consortium, International Parkinson Disease Genomics Consortium, and the Risk and Modifying Factors in FrontoTemporal Dementia Investigators, VU University Medical Center, Amsterdam, Netherlands; VU Medical Center, Amsterdam, Netherlands; Johns Hopkins University School of Medicine, Baltimore, MD, USA; National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA; Amsterdam Neuroscience, Amsterdam, Netherlands; Fundacion Insituto Leloir, Instituto de Investigeciones Bioquimicas de Buenos Aires, National Scientific and Technical Research Council (CONICET), Buenos Aires, Argentina; Department for Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; VU University Medical Center, Alzheimer Center, Amsterdam Neuroscience, Amsterdam, Netherlands; Delft University of Technology, Delft, Netherlands; Barcelona Alzheimer Treatment and Research Center (Fundacio ACE), Barcelona, Spain; Sant PauMemoryUnit, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Aut onoma de Barcelona, Barcelona, Spain; VU University Medical Centre, Amsterdam, Netherlands; Neuroscience Center, Barcelona Alzheimer Treatment and Research Center (Fundacio ACE), Institut Catal a de Neuroci encies Aplicades, Barcelona, Spain; Sant Pau Institute of Biomedical Research, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centre of Biomedical Investigation Network for Neurodegenerative Diseases, Madrid, Spain; University Hospital Marques de Valdecilla, Santander, Spain; Leiden University Medical Center, Leiden, Netherlands; Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; German Center for Neurodegenerative Diseases, T€ubingen, Germany. Contact e-mail: s.j. vanderlee@vumc.nl