Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

affy2sv: an R package to pre-process Affymetrix CytoScan HD and 750K arrays for SNP, CNV, inversion and mosaicism calling.

Background:The well-known Genome-Wide Association Studies (GWAS) had led to many scientific discoveriesusing SNP data. Even so, they were not able to explain the full heritability of complex diseases. Now, other structuralvariants like copy number variants or DNA inversions, either germ-line or in mosaicism events, are being studies.We present the R packageaffy2svto pre-process Affymetrix CytoScan HD/750k array (also for Genome-WideSNP 5.0/6.0 and Axiom) in structural variant studies.Results:We illustrate the capabilities ofaffy2svusing two different complete pipelines on real data. The firstone performing a GWAS and a mosaic alterations detection study, and the other detecting CNVs and performingan inversion calling.Conclusion:Both examples presented in the article show up howaffy2svcan be used as part of more complexpipelines aimed to analyze Affymetrix SNP arrays data in genetic association studies, where different types ofstructural variants are considered.This work was partly supported by the Spanish Ministry of Science and Innovation (MTM2011-26515), FIS PI1002512 and a predoctoral fellowship of the Universitat Pompeu Fabra (to CH-F)

affy2sv: an R package to pre-process Affymetrix CytoScan HD and 750K arrays for SNP, CNV, inversion and mosaicism calling.

Background:The well-known Genome-Wide Association Studies (GWAS) had led to many scientific discoveriesusing SNP data. Even so, they were not able to explain the full heritability of complex diseases. Now, other structuralvariants like copy number variants or DNA inversions, either germ-line or in mosaicism events, are being studies.We present the R packageaffy2svto pre-process Affymetrix CytoScan HD/750k array (also for Genome-WideSNP 5.0/6.0 and Axiom) in structural variant studies.Results:We illustrate the capabilities ofaffy2svusing two different complete pipelines on real data. The firstone performing a GWAS and a mosaic alterations detection study, and the other detecting CNVs and performingan inversion calling.Conclusion:Both examples presented in the article show up howaffy2svcan be used as part of more complexpipelines aimed to analyze Affymetrix SNP arrays data in genetic association studies, where different types ofstructural variants are considered.This work was partly supported by the Spanish Ministry of Science and Innovation (MTM2011-26515), FIS PI1002512 and a predoctoral fellowship of the Universitat Pompeu Fabra (to CH-F)

No major host genetic risk factor contributed to A(H1N1)2009 influenza severity

While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10-8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course.Funding for this work came from Instituto de Salud Carlos III (Madrid, Spain; www.isciii.es) grant GR09/0032

Exon-focused genome-wide association study of obsessive-compulsive disorder and shared polygenic risk with schizophrenia.

Common single-nucleotide polymorphisms (SNPs) account for a large proportion of the heritability of obsessive-compulsive disorder (OCD). Co-ocurrence of OCD and schizophrenia is commoner than expected based on their respective prevalences, complicating the clinical management of patients. This study addresses two main objectives: to identify particular genes associated with OCD by SNP-based and gene-based tests; and to test the existence of a polygenic risk shared with schizophrenia. The primary analysis was an exon-focused genome-wide association study of 370 OCD cases and 443 controls from Spain. A polygenic risk model based on the Psychiatric Genetics Consortium schizophrenia data set (PGC-SCZ2) was tested in our OCD data. A polygenic risk model based on our OCD data was tested on previous data of schizophrenia from our group. The most significant association at the gene-based test was found at DNM3 (P=7.9 × 10(-5)), a gene involved in synaptic vesicle endocytosis. The polygenic risk model from PGC-SCZ2 data was strongly associated with disease status in our OCD sample, reaching its most significant value after removal of the major histocompatibility complex region (lowest P=2.3 × 10(-6), explaining 3.7% of the variance). The shared polygenic risk was confirmed in our schizophrenia data. In conclusion, DNM3 may be involved in risk to OCD. The shared polygenic risk between schizophrenia and OCD may be partially responsible for the frequent comorbidity of both disorders, explaining epidemiological data on cross-disorder risk. This common etiology may have clinical implications.The study was supported by Fundación María José Jove, Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia; and by grants from the Instituto de Salud Carlos III FIS PI13/01136 to AC, CP11/00163 to JC, PI13/00918 to JMM, PI14/00413 to PA; the Generalitat de Catalunya AGAUR 2014 SGR-1138; the Spanish MINIECO SAF2013-49108- R Plan Estatal; and the European Commission 7th Framework Program, Project N. 262055 (ESGI) to XE. LD is supported by a Severo Ochoa fellowship of the Spanish MINIECO