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bioRxiv2016

Origin of modern syphilis and emergence of a contemporary pandemic cluster

Syphilis swept across the world in the 16th century as one of most prominent documented pandemics and is re-emerging worldwide despite the availability of effective antibiotics. Little is known about the genetic patterns in current infections or the evolutionary origins of the disease due to the non-cultivable and clonal nature of the causative bacterium Treponema pallidum subsp. pallidum. In this study, we used DNA capture and next generation sequencing to obtain whole genome data from syphilis patient specimens and from treponemes propagated in laboratory settings. Phylogenetic analyses indicate that the syphilis strains examined here share a common ancestor after the 15th century. Moreover, most contemporary strains are azithromycin resistant and members of a globally dominant cluster named here as SS14-{Omega}. This cluster diversified from a common ancestor in the mid-20th century and has the population genetic and epidemiological features indicative of the emergence of a pandemic strain cluster.

Microbiology↗

bioRxiv2016

Excess of deleterious mutations around HLA genes reveals evolutionary cost of balancing selection

Deleterious mutations are expected to evolve under negative selection and are usually purged from the population. However, deleterious alleles segregate in the human population and some disease-associated variants are maintained at considerable frequencies. Here we test the hypothesis that balancing selection may counteract purifying selection in neighboring regions and thus maintain deleterious variants at higher frequency than expected from their detrimental fitness effect. We first show in realistic simulations that balancing selection reduces the density of polymorphic sites surrounding a locus under balancing selection, but at the same time markedly increases the population frequency of the remaining variants, including even substantially deleterious alleles. To test the predictions of our simulations empirically, we then use whole exome sequencing data from 6,500 human individuals and focus on the most established example for balancing selection in the human genome, the major histocompatibility complex (MHC). Our analysis shows an elevated frequency of putatively deleterious coding variants in non-HLA genes localized in the MHC region. The mean frequency of these variants declined with physical distance from the classical HLA genes, indicating dependency on genetic linkage. These results reveal an indirect cost of the genetic diversity maintained by balancing selection, which has hitherto been perceived as mostly advantageous, and have implications both for the evolution of recombination and also for the epidemiology of various MHC-associated diseases.

Evolutionary Biology↗

bioRxiv2016

A full characterization of evolutionary tree topologies

The shapes of evolutionary trees are influenced by the nature of the evolutionary process, but comparisons of trees from different processes are hindered by the challenge of completely describing tree shape. We present a full characterization of the shapes of rooted branching trees in a form that lends itself to natural tree comparisons. The resulting metric distinguishes trees from random models known to produce different tree shapes. It separates trees derived from tropical vs USA influenza A sequences, which reflect the differing epidemiology of tropical and seasonal flu. We extend the shape metric to incorporate summary features such as asymmetry, or statistics on branch lengths. Our approach allows us to construct addition and multiplication on trees, and to create a convex metric on tree shapes which formally allows computation of average trees.

Evolutionary Biology↗

bioRxiv2016

Zika in Rio de Janeiro: Assessment of basic reproduction number and comparison with dengue outbreaks

Zika virus infection was declared a public health emergency of international concern in February 2016 in response to the outbreak in Brazil and its suspected link with congenital anomalies. In this study we use notification data and disease natural history parameters to estimate the basic reproduction number (R0) of Zika in Rio de Janeiro, Brazil. We also obtain estimates of R0 of dengue from time series of dengue cases in the outbreaks registered in 2002 and 2012 in the city, when DENV-3 and DENV-4 serotypes respectively, had just emerged. Our estimates of the basic reproduction number for Zika in Rio de Janeiro based on surveillance notifications (R0 = 2.33, 95% CI: 1.97 - 2.97) were higher than those obtained for dengue in the city (year 2002: R0 = 1.70 [1.50 - 2.02]; year 2012: Ro = 1.25 [1.18 - 1.36]). Given the role of Aedes aegypti as vector of both the Zika and dengue viruses, we also derive Ro of Zika as a function of both dengue reproduction number and entomological and epidemiological parameters for dengue and Zika. Using the dengue outbreaks from previous years allowed us to estimate the potential R0 of Zika. Our estimates were closely in agreement with our first Zikas R0 estimation from notification data. Hence, these results validate deriving the potential risk of Zika transmission in areas with recurring dengue outbreaks. Whether transmission routes other than vector-based can sustain a Zika epidemic still deserves attention, but our results suggest that the Zika outbreak in Rio de Janeiro emerged due to population susceptibility and ubiquitous presence of Ae. aegypti.

Scientific Communication and Education↗

bioRxiv2016

Report of Partial findings from the National Toxicology Program Carcinogenesis Studies of Cell Phone Radiofrequency Radiation in Hsd: Sprague Dawley® SD rats (Whole Body Exposure)

The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Programs cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.\n\nSUMMARYThe purpose of this communication is to report partial findings from a series of radiofrequency radiation (RFR) cancer studies in rats performed under the auspices of the U.S. National Toxicology Program (NTP).1 This report contains peer-reviewed, neoplastic and hyperplastic findings only in the brain and heart of Hsd:Sprague Dawley(R) SD(R) (HSD) rats exposed to RFR starting in utero and continuing throughout their lifetimes. These studies found low incidences of malignant gliomas in the brain and schwannomas in the heart of male rats exposed to RFR of the two types [Code Division Multiple Access (CDMA) and Global System for Mobile Communications (GSM)] currently used in U.S. wireless networks. Potentially preneoplastic lesions were also observed in the brain and heart of male rats exposed to RFR.\n\nThe review of partial study data in this report has been prompted by several factors. Given the widespread global usage of mobile communications among users of all ages, even a very small increase in the incidence of disease resulting from exposure to RFR could have broad implications for public health. There is a high level of public and media interest regarding the safety of cell phone RFR and the specific results of these NTP studies. Lastly, the tumors in the brain and heart observed at low incidence in male rats exposed to GSM-and CDMA-modulated cell phone RFR in this study are of a type similar to tumors observed in some epidemiology studies of cell phone use. These findings appear to support the International Agency for Research on Cancer (IARC) conclusions regarding the possible carcinogenic potential of RFR.2\n\nIt is important to note that this document reviews only the findings from the brain and heart and is not a complete report of all findings from the NTPs studies. Additional data from these studies in Hsd:Sprague Dawley(R) SD(R) (Harlan) rats and similar studies conducted in B6C3F1/N mice are currently under evaluation and will be reported together with the current findings in two forthcoming NTP Technical Reports.

Cancer Biology↗

bioRxiv2016

Polygenic scores using summary statistics via penalized regression

Polygenic scores (PGS) summarize the genetic contribution of a persons genotype to a disease or phenotype. They can be used to group participants into different risk categories for diseases, and are also used as covariates in epidemiological analyses. A number of possible ways of calculating polygenic scores have been proposed, and recently there is much interest in methods that incorporate information available in published summary statistics. As there is no inherent information on linkage disequilibrium (LD) in summary statistics, a pertinent question is how we can make use of LD information available elsewhere to supplement such analyses. To answer this question we propose a method for constructing PGS using summary statistics and a reference panel in a penalized regression framework, which we call lassosum. We also propose a general method for choosing the value of the tuning parameter in the absence of validation data. In our simulations, we showed that pseudovalidation often resulted in prediction accuracy that is comparable to using a dataset with validation phenotype and was clearly superior to the conservative option of setting the tuning parameter of lassosum to its lowest value. We also showed that lassosum achieved better prediction accuracy than simple clumping and p-value thresholding in almost all scenarios. It was also substantially faster and more accurate than the recently proposed LDpred.

Genomics↗

bioRxiv2016

Atypical Salmonella enterica serovars in murine and human infection models: Is it time to reassess our approach to the study of salmonellosis?

Nontyphoidal Salmonella species are globally disseminated pathogens and the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied using in vivo murine models and cell lines typically challenged with Salmonella Typhimurium. Although serovars Enteritidis and Typhimurium are responsible for the most of human infections reported to the CDC, several other serovars also contribute to clinical cases of salmonellosis. Despite their epidemiological importance, little is known about their infection phenotypes. Here, we report the virulence characteristics and genomes of 10 atypical S. enterica serovars linked to multistate foodborne outbreaks in the United States. We show that the murine RAW 264.7 macrophage model of infection is unsuitable for inferring human relevant differences in nontyphoidal Salmonella infections whereas differentiated human THP-1 macrophages allowed these isolates to be further characterised in a more relevant, human context.

Microbiology↗

bioRxiv2016

Genomic dissection of an Icelandic epidemic of equine respiratory disease

The native horse population of Iceland has remained free of major infectious diseases. Between May and July 2010 an epidemic of respiratory disease swept through the population. Initial microbiological investigations ruled out known equine viral agents as the cause of the infections, but identified the opportunistic pathogen Streptococcus zooepidemicus as being frequently isolated from diseased animals. This diverse bacterial species has a broad host range and is usually regarded as a commensal of horses. By genome sequencing S. zooepidemicus recovered from horses during the epidemic we show that although multiple clones of S. zooepidemicus were present in the population, one particular clone, ST209, was responsible for the epidemic. Concurrent with the epidemic, ST209 caused zoonotic infections, highlighting the pathogenic potential of this clone. Phylogenetic analysis suggests that the original ST209 strain entered Iceland in late 2008 or early 2009. Epidemiological investigation revealed that the incursion of this strain into a training yard that utilized a submerged treadmill between the 5th and 19th of February 2010 was a critical trigger for the ensuing epidemic of disease, provided a nidus for the infection of multiple horses, and subsequent distribution of these animals to multiple sites in Iceland.

Microbiology↗

bioRxiv2016

Using reference-free compressed data structures to analyse sequencing reads from thousands of human genomes

We are rapidly approaching the point where we have sequenced millions of human genomes. There is a pressing need for new data structures to store raw sequencing data and efficient algorithms for population scale analysis. Current reference based data formats do not fully exploit the redundancy in population sequencing nor take advantage of shared genetic variation. In recent years, the Burrows-Wheeler transform (BWT) and FM-index have been widely employed as a full text searchable index for read alignment and de novo assembly. We introduce the concept of a population BWT and use it to store and index the sequencing reads of 2,705 samples from the 1000 Genomes Project. A key feature is that as more genomes are added, identical read sequences are increasingly observed and compression becomes more efficient. We assess the support in the 1000 Genomes read data for every base position of two human reference assembly versions, identifying that 3.2 Mbp with population support was lost in the transition from GRCh37 with 13.7 Mbp added to GRCh38. We show that the vast majority of variant alleles can be uniquely described by overlapping 31-mers and show how rapid and accurate SNP and indel genotyping can be carried out across the genomes in the population BWT. We use the population BWT to carry out non-reference queries to search for the presence of all known viral genomes, and discover human T-lymphotropic virus 1 integrations in six samples in a recognised epidemiological distribution.

Genomics↗

bioRxiv2016

The queenslandensis and the type form of the dengue fever mosquito (Aedes aegypti L.) are genomically indistinguishable

BackgroundThe mosquito Aedes aegypti (L.) is a major vector of viral diseases like dengue fever, Zika and chikungunya. Aedes aegypti exhibits high morphological and behavioral variation, some of which is thought to be of epidemiological significance. Globally distributed domestic Ae. aegypti have been traditionally grouped into (i) the very pale variety queenslandensis and (ii) the type form. Because the two color forms co-occur across most of their range, there is interest in understanding how freely they interbreed. This knowledge is particularly important for control strategies that rely on mating compatibilities between the release and target mosquitoes, such as Wolbachia releases and SIT. To answer this question, we analyzed nuclear and mitochondrial genome-wide variation in the co-occurring pale and type Ae. aegypti from northern Queensland (Australia) and Singapore.\n\nMethods/FindingsWe typed 74 individuals at a 1170 bp-long mitochondrial sequence and at 16,569 nuclear SNPs using a customized double-digest RAD sequencing. 11/29 genotyped individuals from Singapore and 11/45 from Queensland were identified as var. queenslandensis based on the diagnostic scaling patterns. We found 24 different mitochondrial haplotypes, seven of which were shared between the two forms. Multivariate genetic clustering based on nuclear SNPs corresponded to individuals geographic location, not their color. Several family groups consisted of both forms and three queenslandensis individuals were Wolbachia infected, indicating previous breeding with the type form which has been used to introduce Wolbachia into Ae. aegypti populations.\n\nConclusionAedes aegypti queenslandensis are genomically indistinguishable from the type form, which points to these forms freely interbreeding at least in Australia and Singapore. Based on our findings, it is unlikely that the presence of very pale Ae. aegypti will affect the success of Aedes control programs based on Wolbachia-infected, sterile or RIDL mosquitoes.\n\nAuthor SummaryAedes aegypti, the most important vector of dengue and Zika, greatly varies in body color and behavior. Two domestic forms of this mosquito, the very pale queenslandensis and the browner type, are often found together in populations around the globe. Knowing how freely they interbreed is important for the control strategies such as releases of Wolbachia and sterile males. To answer this question, we used RAD sequencing to genotype samples of both forms collected in Singapore and northern Queensland. We did not find any association between the mitochondrial or nuclear genome-wide variation and color variation in these populations. Rather, \"paleness\" is likely to be a quantitative trait under some environmental influence. We also detected several queenslandensis individuals with the Wolbachia infection, indicating free interbreeding with the type form which has been used to introduce Wolbachia into Ae. aegypti populations. Overall, our data show that the very pale queenslandensis are not genomically separate, and their presence is unlikely to affect the success of Aedes control programs based on Wolbachia-infected, sterile or RIDL mosquitoes.

Genomics↗

bioRxiv2016

Impact of Sample Type and DNA Isolation Procedure on Genomic Inference of Microbiome Composition

Explorations of complex microbiomes using genomics greatly enhance our understanding about their diversity, biogeography, and function. The isolation of DNA from microbiome specimens is a key prerequisite for such examinations, but challenges remain in obtaining sufficient DNA quantities required for certain sequencing approaches, achieving accurate genomic inference of microbiome composition, and facilitating comparability of findings across specimen types and sequencing projects. These aspects are particularly relevant for the genomics-based global surveillance of infectious agents and antimicrobial resistance from different reservoirs. Here, we compare in a stepwise approach a total of eight commercially available DNA extraction kits and 16 procedures based on these for three specimen types (human feces, pig feces, and hospital sewage). We assess DNA extraction using spike-in controls, and different types of beads for bead-beating facilitating cell lysis. We evaluate DNA concentration, purity, and stability, and microbial community composition using 16S rRNA gene sequencing and for selected samples using shotgun metagenomic sequencing. Our results suggest that inferred community composition was dependent on inherent specimen properties as well as DNA extraction method. We further show that bead-beating or enzymatic treatment can increase the extraction of DNA from Gram-positive bacteria. Final DNA quantities could be increased by isolating DNA from a larger volume of cell lysate compared to standard protocols. Based on this insight, we designed an improved DNA isolation procedure optimized for microbiome genomics that can be used for the three examined specimen types and potentially also for other biological specimens. A standard operating procedure is available from: https://dx.doi.org/10.6084/m9.figshare.3475406.\n\nIMPORTANCESequencing-based analyses of microbiomes may lead to a breakthrough in our understanding of the microbial world associate with humans, animals, and the environment. Such insight could further the development of innovative ecosystem management approaches for the protection of our natural resources, and the design of more effective and sustainable solutions to prevent and control infectious diseases. Genome sequence information is an organism- (pathogen-) independent language that can be used across sectors, space, and time. Harmonized standards, protocols, and workflows for sample processing and analysis can facilitate the generation of such actionable information. In this study, we assessed several procedures for the isolation of DNA for next-generation sequencing. Our study highlights several important aspects to consider in the design and conduction of sequence-based analysis of microbiomes. We provide a standard operating procedure for the isolation of DNA from a range of biological specimens particularly relevant in clinical diagnostics and epidemiology.

Microbiology↗

bioRxiv2016

Population and individual effects of non-coding variants inform genetic risk factors

Identifying functional non-coding variants can enhance genome interpretation and inform novel genetic risk factors. We used whole genomes and peripheral white blood cell transcriptomes from 624 Sardinian individuals to identify non-coding variants that contribute to population, family, and individual differences in transcript abundance. We identified 21,183 independent expression quantitative trait loci (eQTLs) and 6,768 independent splicing quantitative trait loci (sQTLs) influencing 73 and 41% of all tested genes. When we compared Sardinian eQTLs to those previously identified in Europe, we identified differentiated eQTLs at genes involved in malarial resistance and multiple sclerosis, reflecting the long-term epidemiological history of the islands population. Taking advantage of pedigree data for the population sample, we identify segregating patterns of outlier gene expression and allelic imbalance in 61 Sardinian trios. We identified 809 expression outliers (median z-score of 2.97) averaging 13.3 genes with outlier expression per individual. We then connected these outlier expression events to rare non-coding variants. Our results provide new insight into the effects of non-coding variants and their relationship to population history, traits and individual genetic risk.

Genomics↗

bioRxiv2016

Whole genome sequencing of Plasmodium falciparum from dried blood spots using selective whole genome amplification

Translating genomic technologies into healthcare applications for the malaria parasite Plasmodium falciparum has been limited by the technical and logistical difficulties of obtaining high quality clinical samples from the field. Sampling by dried blood spot (DBS) finger-pricks can be performed safely and efficiently with minimal resource and storage requirements compared with venous blood (VB). Here, we evaluate the use of selective whole genome amplification (sWGA) to sequence the P. falciparum genome from clinical DBS samples, and compare the results to current methods using leucodepleted VB. Parasite DNA with high (> 95%) human DNA contamination was selectively amplified by Phi29 polymerase using short oligonucleotide probes of 8-12 mers as primers. These primers were selected on the basis of their differential frequency of binding the desired (P. falciparum DNA) and contaminating (human) genomes. Using sWGA method, we sequenced clinical samples from 156 malaria patients, including 120 paired samples for head-to-head comparison of DBS and leucodepleted VB. Greater than 18-fold enrichment of P. falciparum DNA was achieved from DBS extracts. The parasitaemia threshold to achieve >5x coverage for 50% of the genome was 0.03% (40 parasites per 200 white blood cells). Over 99% SNP concordance between VB and DBS samples was achieved after excluding missing calls. The sWGA methods described here provide a reliable and scalable way of generating P. falciparum genome sequence data from DBS samples. Our data indicate that it will be possible to get good quality sequence data on most if not all drug resistance loci from the majority of symptomatic malaria patients. This technique overcomes a major limiting factor in P. falciparum genome sequencing from field samples, and paves the way for large-scale epidemiological applications.

Genomics↗

bioRxiv2016

Pollutants and insecticides drive local adaptation in African malaria mosquitoes

The Anopheles gambiae complex contains a number of highly anthropophilic mosquito species that have acquired exceptional ability to thrive in complex human habitats. Thus, examining the evolutionary history of this Afrotropical mosquito may yield vital information on the selective processes that occurred during the adaptation to human-dominated environments. We performed reduced representation sequencing on 941 mosquitoes of the Anopheles gambiae complex collected across four ecogeographic zones in Cameroon. We find evidence for genetic and geographic subdivision within An. coluzzii and An. gambiae sensu stricto - the two most significant malaria vectors in the region. Importantly, in both species, rural and urban populations are genetically differentiated. Genome scans reveal pervasive signatures of selection centered on genes involved in xenobiotic resistance. Notably, a selective sweep containing detoxification enzymes is prominent in urban mosquitoes that exploit polluted breeding sites. Overall, our study suggests that recent anthropogenic environmental modifications and widespread use of insecticides are driving population differentiation and local adaptation in vectors with potentially significant consequences for malaria epidemiology.

Evolutionary Biology↗

bioRxiv2016

Interactive online brain shape visualization

Urbanization presents unique environmental challenges to human commensal species. The Afrotropical Anopheles gambiae complex contains a number of synanthropic mosquito species that are major vectors of malaria. To examine ongoing cryptic diversification within the complex, we performed reduced representation sequencing on 941 mosquitoes collected across four ecogeographic zones in Cameroon. We find evidence for clear subdivision within An. coluzzii and An. gambiae s.s. - the two most significant malaria vectors in the region. Importantly, in both species rural and urban populations of mosquitoes were genetically differentiated. Genome scans of cryptic subgroups reveal pervasive signatures of selection centered on genes involved in xenobiotic resistance. Notably, a selective sweep containing eight detoxification enzymes is unique to urban mosquitoes that exploit polluted breeding sites. Overall, our study reveals that anthropogenic environmental modification is driving population differentiation and local adaptation in African malaria mosquitoes with potentially significant consequences for malaria epidemiology.

Bioinformatics↗

bioRxiv2016

Novel blaKPC-carrying species identified in the hospital environment

blaKPC, encoding one of five dominant global carbapenemase families, is increasingly identified in environmental species difficult to characterize using routine diagnostic methods, with epidemiological and clinical implications. During environmental hospital infection prevention and control investigations (Manchester, UK) we used whole genome sequencing to confirm species identification for isolates infrequently associated with blaKPC and/or difficult to classify by MALDI-ToF. Four previously undescribed blaKPC-carrying species were identified from the hospital environment, including a putative, novel Enterobacter species.

Microbiology↗

bioRxiv2016

Genetic correlations among brain-behavioral and immune-related phenotypes based on genome-wide association data.

Individuals with psychiatric disorders have elevated rates of autoimmune comorbidity and altered immune signaling. It is unclear whether these altered immunological states have a shared genetic basis with those psychiatric disorders. The present study sought to use existing summary-level data from previous genome-wide association studies (GWASs) to determine if commonly varying single nucleotide polymorphisms (SNPs) are shared between psychiatric and immune-related phenotypes. We estimated heritability and examined pair-wise genetic correlations using the linkage disequilibrium score regression (LDSC) and heritability estimation from summary statistics (HESS) methods. Using LDSC, we observed significant genetic correlations between immune-related disorders and several psychiatric disorders, including anorexia nervosa, attention deficit-hyperactivity disorder, bipolar disorder, major depression, obsessive compulsive disorder, schizophrenia, smoking behavior, and Tourette syndrome. Loci significantly mediating genetic correlations were identified for schizophrenia when analytically paired with Crohns disease, primary biliary cirrhosis, systemic lupus erythematosus, and ulcerative colitis. We report significantly correlated loci and highlight those containing genome-wide associations and candidate genes for respective disorders. We also used the LDSC method to characterize genetic correlations amongst the immune-related phenotypes. We discuss our findings in the context of relevant genetic and epidemiological literature, as well as the limitations and caveats of the study.

Bioinformatics↗

bioRxiv2016

Personalized genetic assessment of age associated Alzheimers disease risk

ImportanceIdentifying individuals at risk for developing Alzheimers disease (AD) is of utmost importance. Although genetic studies have identified APOE and other AD associated single nucleotide polymorphisms (SNPs), genetic information has not been integrated into an epidemiological framework for personalized risk prediction.\n\nObjectiveTo develop, replicate and validate a novel polygenic hazard score for predicting age-specific risk for AD.\n\nSettingMulti-center, multi-cohort genetic and clinical data.\n\nParticipantsWe assessed genetic data from 17,008 AD patients and 37,154 controls from the International Genetics of Alzheimers Project (IGAP), and 6,409 AD patients and 9,386 older controls from Phase 1 Alzheimers Disease Genetics Consortium (ADGC). As independent replication and validation cohorts, we also evaluated genetic, neuroimaging, neuropathologic, CSF and clinical data from ADGC Phase 2, National Institute of Aging Alzheimers Disease Center (NIA ADC) and Alzheimers Disease Neuroimaging Initiative (ADNI) (total n = 20,680)\n\nMain Outcome(s) and Measure(s)Use the IGAP cohort to first identify AD associated SNPs (at p < 10-5). Next, integrate these AD associated SNPs into a Cox proportional hazards model using ADGC phase 1 genetic data, providing a polygenic hazard score (PHS) for each participant. Combine population based incidence rates, and genotype-derived PHS for each individual to derive estimates of instantaneous risk for developing AD, based on genotype and age. Finally, assess replication and validation of PHS in independent cohorts.\n\nResultsIndividuals in the highest PHS quantiles developed AD at a considerably lower age and had the highest yearly AD incidence rate. Among APOE {varepsilon}3/3 individuals, PHS modified expected age of AD onset by more than 10 years between the lowest and highest deciles. In independent cohorts, PHS strongly predicted empirical age of AD onset (p = 1.1 x 10-26), longitudinal progression from normal aging to AD (p = 1.54 x 10-10) and associated with markers of AD neurodegeneration.\n\nConclusionsWe developed, replicated and validated a clinically usable PHS for quantifying individual differences in age-specific risk of AD. Beyond APOE, polygenic architecture plays an important role in modifying AD risk. Precise quantification of AD genetic risk will be useful for early diagnosis and therapeutic strategies.

Genetics↗