| 1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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. Methods: 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. Results: 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). Conclusions: 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. © 2021 Society of Biological Psychiatry
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| 13. |
- Jia, X. M., et al.
(författare)
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Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:9, s. 5239-5250
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 x 10(-4)), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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| 15. |
- Gonze, X., et al.
(författare)
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Recent developments in the ABINIT software package
- 2016
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Ingår i: Computer Physics Communications. - : Elsevier BV. - 0010-4655. ; 205, s. 106-131
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Tidskriftsartikel (refereegranskat)abstract
- ABINIT is a package whose main program allows one to find the total energy, charge density, electronic structure and many other properties of systems made of electrons and nuclei, (molecules and periodic solids) within Density Functional Theory (DFT), Many-Body Perturbation Theory (GW approximation and Bethe-Salpeter equation) and Dynamical Mean Field Theory (DMFT). ABINIT also allows to optimize the geometry according to the DFT forces and stresses, to perform molecular dynamics simulations using these forces, and to generate dynamical matrices, Born effective charges and dielectric tensors. The present paper aims to describe the new capabilities of ABINIT that have been developed since 2009. It covers both physical and technical developments inside the ABINIT code, as well as developments provided within the ABINIT package. The developments are described with relevant references, input variables, tests and tutorials. Program summary: . Program title: ABINIT. . Catalogue identifier: AEEU_v2_0. . Program summary URL: . http://cpc.cs.qub.ac.uk/summaries/AEEU_v2_0.html . . Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland. . Licensing provisions: GNU General Public License, version 3. . No. of lines in distributed program, including test data, etc.: 4845789. . No. of bytes in distributed program, including test data, etc.: 71340403. . Distribution format: tar.gz. . Programming language: Fortran2003, PERL scripts, Python scripts. . Classification: 7.3, 7.8. . External routines: (all optional) BigDFT [2], ETSF_IO [3], libxc [4], NetCDF [5], MPI [6], Wannier90 [7], FFTW [8]. . Catalogue identifier of previous version: AEEU_v1_0. . Journal reference of previous version: Comput. Phys. Comm. 180 (2009) 2582. . Does the new version supersede the previous version?: Yes. The abinit-7.10.5 version is now the up to date stable version of ABINIT. . Nature of problem: . This package has the purpose of computing accurately material and nanostructure properties: electronic structure, bond lengths, bond angles, primitive cell size, cohesive energy, dielectric properties, vibrational properties, elastic properties, optical properties, magnetic properties, non-linear couplings, electronic and vibrational life-times, and others. . Solution method: . Software application based on Density Functional Theory, Many-Body Perturbation Theory and Dynamical Mean Field Theory, pseudopotentials, with plane waves or wavelets as basis functions. . Reasons for new version: . Since 2009, the abinit-5.7.4 version of the code has considerably evolved and is not yet up to date. The abinit- 7.10.5 version contains new physical and technical features that allow electronic structure calculations impossible to carry out in the previous versions. . Summary of revisions: . •new physical features: quantum effects for the nuclei treated by the Path-integral Molecular Dynamics; finding transition states using image dynamics (NEB or string methods); two component DFT for electron-positron annihilation; linear response in a Projector Augmented-Wave approach -PAW-, electron-phonon interactions and temperature dependence of the gap; Bethe Salpeter Equation -BSE-; Dynamical Mean Field Theory (DMFT).•new technical features: development of a PAW approach for a wavelet basis; parallelisation of the code on more than 10,000 processors; new build system.•new features in the ABINIT package: tests; test farm; new tutorials; new pseudopotentials and PAW atomic data tables; GUI and postprocessing tools like the AbiPy and APPA libraries. . Running time: . It is difficult to answer to the question as the use of ABINIT is very large. On one hand, ABINIT can run on 10,000 processors for hours to perform quantum molecular dynamics on large systems. On the other hand, tutorials for students can be performed on a laptop within a few minutes. . References: . 1 http://www.gnu.org/copyleft/gpl.txt 2 http://bigdft.org 3 http://www.etsf.eu/fileformats 4 http://www.tddft.org/programs/octopus/wiki/index.php/Libxc 5 http://www.unidata.ucar.edu/software/netcdf 6 https://en.wikipedia.org/wiki/Message_Passing_Interface 7 http://www.wannier.org 8M. Frigo and S.G. Johnson, Proceedings of the IEEE, 93, 216-231 (2005). . .
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| 17. |
- Bigdeli, TB, et al.
(författare)
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Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry
- 2020
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 25:10, s. 2455-2467
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke’s R2 = 0.032; liability R2 = 0.017; P < 10−52), Latino (Nagelkerke’s R2 = 0.089; liability R2 = 0.021; P < 10−58), and European individuals (Nagelkerke’s R2 = 0.089; liability R2 = 0.037; P < 10−113), further highlighting the advantages of incorporating data from diverse human populations.
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| 18. |
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| 19. |
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| 20. |
- Parma, Valentina, et al.
(författare)
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More Than Smell—COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis
- 2020
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Ingår i: Chemical Senses. - : Oxford University Press (OUP). - 0379-864X .- 1464-3553. ; 45:7, s. 609-622
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Tidskriftsartikel (refereegranskat)abstract
- Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19–79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (−79.7 ± 28.7, mean ± standard deviation), taste (−69.0 ± 32.6), and chemesthetic (−37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.
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| 21. |
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| 22. |
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| 23. |
- Genovese, G., et al.
(författare)
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Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
- 2016
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 19:11, s. 1433-1441
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Tidskriftsartikel (refereegranskat)abstract
- By analyzing the exomes of 12,332 unrelated Swedish individuals, including 4,877 individuals affected with schizophrenia, in ways informed by exome sequences from 45,376 other individuals, we identified 244,246 coding-sequence and splice-site ultra-rare variants (URVs) that were unique to individual Swedes. We found that gene-disruptive and putatively protein-damaging URVs (but not synonymous URVs) were more abundant among individuals with schizophrenia than among controls (P = 1.3 x 10(-10)). This elevation of protein-compromising URVs was several times larger than an analogously elevated rate for de novo mutations, suggesting that most rare-variant effects on schizophrenia risk are inherited. Among individuals with schizophrenia, the elevated frequency of protein-compromising URVs was concentrated in brain-expressed genes, particularly in neuronally expressed genes; most of this elevation arose from large sets of genes whose RNAs have been found to interact with synaptically localized proteins. Our results suggest that synaptic dysfunction may mediate a large fraction of strong, individually rare genetic influences on schizophrenia risk.
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| 27. |
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| 28. |
- Holm Nielsen, S., et al.
(författare)
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A biomarker of collagen type I degradation is associated with cardiovascular events and mortality in patients with atherosclerosis
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820. ; 285:1, s. 118-123
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Atherosclerosis is characterized by accumulation of lipids, cells and extracellular matrix (ECM) proteins in the arterial wall. Collagen type I (COL1), a component of the arterial ECM, is cleaved by matrix metalloproteinases (MMPs) and known to be remodelled in atherosclerosis. We explored whether the MMP-mediated COL1 biomarker, C1M, was associated with cardiovascular events, cardiovascular mortality and all-cause mortality in a large prospective cohort of patients with known atherosclerosis. Methods: Serum from 787 patients who underwent a carotid endarterectomy was included. Circulating levels of C1M were measured in serum. A total of 473 patients were followed for 6 years after surgery. Associations between C1M and incidence of cardiovascular events, cardiovascular mortality and all-cause mortality were assessed by Kaplan–Meier curves and Cox regression analysis. Results: A total of 101 (21.4%) patients suffered from nonfatal cardiovascular events during the follow-up period, and 64 (13.5%) patients died. Of these, 39 (60.9%) died from cardiovascular diseases. Patients with C1M levels above the median were significantly associated with cardiovascular events, cardiovascular mortality and all-cause mortality (P < 0.001, P = 0.004 and P < 0.001, respectively). C1M was included in the final model for prediction of cardiovascular events (HR 2.15, 95% CI 1.40–3.32, P = 0.001), cardiovascular mortality (HR 2.20, 95% CI 1.07–4.51, P = 0.031) and all-cause mortality (HR 2.98 95% CI 1.67–5.33, P = < 0.001). Conclusions: In patients with atherosclerotic carotid lesions, high levels of C1M predicted cardiovascular events, cardiovascular mortality and all-cause mortality. These findings emphasize the importance of remodelling mechanisms in atherosclerosis that are now becoming more and more explored.
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| 29. |
- Holm Nielsen, S., et al.
(författare)
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The novel collagen matrikine, endotrophin, is associated with mortality and cardiovascular events in patients with atherosclerosis
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 290:1, s. 179-189
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rupture of atherosclerotic plaques is the major cause of acute cardiovascular events. The biomarker PRO-C6 measuring Endotrophin, a matrikine of collagen type VI, may provide valuable information detecting subjects in need of intensified strategies for secondary prevention. Objective: In this study, we evaluate endotrophin in human atherosclerotic plaques and circulating levels of PRO-C6 in patients with atherosclerosis, to determine the predictive potential of the biomarker. Methods: Sections from the stenotic human carotid plaques were stained with the PRO-C6 antibody. PRO-C6 was measured in serum of patients enrolled in the Carotid Plaque Imagining Project (CPIP) (discovery cohort, n = 577) and the innovative medicines initiative surrogate markers for micro- and macrovascular hard end-points for innovative diabetes tools (IMI-SUMMIT, validation cohort, n = 1,378). Median follow-up was 43 months. Kaplan–Meier curves and log-rank tests were performed in the discovery cohort. Cox proportional hazard regression analysis (HR with 95% CI) was used in the discovery cohort and binary logistic regression (OR with 95% CI) in the validation cohort. Results: PRO-C6 was localized in the core and shoulder of the atherosclerotic plaque. In the discovery cohort, PRO-C6 independently predicted future cardiovascular events (HR 1.089 [95% CI 1.019 −1.164], p = 0.01), cardiovascular death (HR 1.118 [95% CI 1.008 −1.241], p = 0.04) and all-cause death (HR 1.087 [95% CI 1.008 −1.172], p = 0.03). In the validation cohort, PRO-C6 predicted future cardiovascular events (OR 1.063 [95% CI 1.011 −1.117], p = 0.017). Conclusion: PRO-C6 is present in the atherosclerotic plaque and associated with future cardiovascular events, cardiovascular death and all-cause mortality in two large prospective cohorts.
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| 30. |
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| 31. |
- Kunkel, E J, et al.
(författare)
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Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity
- 2000
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Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 192:5, s. 761-768
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Tidskriftsartikel (refereegranskat)abstract
- The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.
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| 32. |
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| 33. |
- Legge, SE, et al.
(författare)
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Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia
- 2018
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Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 23:1, s. 162-163
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Tidskriftsartikel (refereegranskat)abstract
- Correction to: Molecular Psychiatry (2017) 22: 1502-1508; advance online publication, 12 July 2017; doi: 10.1038/mp.2016.97 In the first paragraph of the Results section and Figure 1, the authors incorrectly referred to the finding of SNP rs77897117. The correct SNP is rs77897177. The corrected figure appears in previous page.
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| 34. |
- Lejaeghere, Kurt, et al.
(författare)
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Reproducibility in density functional theory calculations of solids.
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 351:6280, s. 1415-1422
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Tidskriftsartikel (refereegranskat)abstract
- The widespread popularity of density functional theory has given rise to an extensive range of dedicated codes for predicting molecular and crystalline properties. However, each code implements the formalism in a different way, raising questions about the reproducibility of such predictions. We report the results of a community-wide effort that compared 15 solid-state codes, using 40 different potentials or basis set types, to assess the quality of the Perdew-Burke-Ernzerhof equations of state for 71 elemental crystals. We conclude that predictions from recent codes and pseudopotentials agree very well, with pairwise differences that are comparable to those between different high-precision experiments. Older methods, however, have less precise agreement. Our benchmark provides a framework for users and developers to document the precision of new applications and methodological improvements.
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| 39. |
- Stankowska, Wiktoria, et al.
(författare)
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Tumor Predisposing Post-Zygotic Chromosomal Alterations in Bladder Cancer-Insights from Histologically Normal Urothelium
- 2024
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Bladder urothelial carcinoma (BLCA) is the 10th most common cancer with a low survival rate and strong male bias. We studied the field cancerization in BLCA using multi-sample- and multi-tissue-per-patient protocol for sensitive detection of autosomal post-zygotic chromosomal alterations and loss of chromosome Y (LOY). We analysed 277 samples of histologically normal urothelium, 145 tumors and 63 blood samples from 52 males and 15 females, using the in-house adapted Mosaic Chromosomal Alterations (MoChA) pipeline. This approach allows identification of the early aberrations in urothelium from BLCA patients. Overall, 45% of patients exhibited at least one alteration in at least one normal urothelium sample. Recurrence analysis resulted in 16 hotspots composed of either gains and copy number neutral loss of heterozygosity (CN-LOH) or deletions and CN-LOH, encompassing well-known and new BLCA cancer driver genes. Conservative assessment of LOY showed 29%, 27% and 18% of LOY-cells in tumors, blood and normal urothelium, respectively. We provide a proof of principle that our approach can characterize the earliest alterations preconditioning normal urothelium to BLCA development. Frequent LOY in blood and urothelium-derived tissues suggest its involvement in BLCA.
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| 40. |
- Thompson, Deborah J, et al.
(författare)
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Genetic predisposition to mosaic Y chromosome loss in blood
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 575, s. 652-657
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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| 41. |
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| 42. |
- Zaitlen, Noah, et al.
(författare)
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Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1x10(-9)). The improvement varied across diseases with a 16% median increase in chi(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
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