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Valerio Napolioni

Università degli studi di Camerino UNICAM, School of Biosciences and veterinary medicine, Faculty Member

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Dr. Napolioni is Associate Professor of Molecular Biology at the School of Biosciences and Veterinary Medicine of the University of Camerino, Italy, where he directs the "Genomic and Molecular Epidemiology (GAME)" laboratory, dealing with the analysis of genomic BIG-DATA and personalized medicine.
Dr. Napolioni holds a PhD in Genetics from the University of Camerino, Italy, working on the genetics of complex traits, focusing on both human longevity and autism. His interest in neuropsychiatric traits led him to continue working on the genetics of autism, first as a post-Doc fellow at the Molecular Psychiatry Lab., “Campus Bio-Medico” University of Rome, and then as Adjan Faculty/Visiting researcher (2011-2012) at the Translational Genomics Research Institute (TGen), Phoenix, AZ, USA In 2013 he became Technical Director of the NGS core at the University of Perugia, Italy. Since 2015 he joined the Department of Neurology and Neurological Sciences of the Stanford University School of Medicine, Palo Alto, CA, first as a post-Doc (2015-2017), and subsequently (2017-2020) as Instructor in Neurology and Neurological Sciences, pursuing his strong research interest in the genetics of human neuropsychiatric and behavioral traits.
Currently, his broad and solid experience in genomic and molecular epidemiology is leading him to address a myriad of different scientific questions, from the analysis of the human to human adaptation to pan-genomic analysis of clinically relevant bacterial species.
Dr. Napolioni is Senior Editor of BMC Medical Genomics and Editorial Board Member of other scientific journals indexed in PubMed and Scopus. He is the author of 116 international publications, including JAMA, Nature Medicine, Nature Genetics, Nature Communications and JAMA Neurology, and has a Scopus H-Index of 32.
Phone: +393334307577
Address: Via Gentile III da Varano, 62032, Camerino

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Papers by Valerio Napolioni

Genome-wide expression of the residual lung reacting to experimental Pneumonectomy

BMC Genomics, Dec 6, 2021

Dog–human translational genomics: state of the art and genomic resources

Journal of Applied Genetics, Sep 8, 2022

PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data

Briefings in Bioinformatics, Dec 8, 2020

The identification of rare haplotypes may greatly expand our knowledge in the genetic architectur... more The identification of rare haplotypes may greatly expand our knowledge in the genetic architecture of both complex and monogenic traits. To this aim, we developed PERHAPS (Paired-End short Reads-based HAPlotyping from next-generation Sequencing data), a new and simple approach to directly call haplotypes from short-read, paired-end Next Generation Sequencing (NGS) data. To benchmark this method, we considered the APOE classic polymorphism (*1/*2/*3/*4), since it represents one of the best examples of functional polymorphism arising from the haplotype combination of two Single Nucleotide Polymorphisms (SNPs). We leveraged the big Whole Exome Sequencing (WES) and SNP-array data obtained from the multi-ethnic UK BioBank (UKBB, N=48,855). By applying PERHAPS, based on piecing together the paired-end reads according to their FASTQ-labels, we extracted the haplotype data, along with their frequencies and the individual diplotype. Concordance rates between WES directly called diplotypes and the ones generated through statistical pre-phasing and imputation of SNP-array data are extremely high (&gt;99%), either when stratifying the sample by SNP-array genotyping batch or self-reported ethnic group. Hardy-Weinberg Equilibrium tests and the comparison of obtained haplotype frequencies with the ones available from the 1000 Genome Project further supported the reliability of PERHAPS. Notably, we were able to determine the existence of the rare APOE*1 haplotype in two unrelated African subjects from UKBB, supporting its presence at appreciable frequency (approximatively 0.5%) in the African Yoruba population. Despite acknowledging some technical shortcomings, PERHAPS represents a novel and simple approach that will partly overcome the limitations in direct haplotype calling from short read-based sequencing.

A Fast and Robust Strategy to Remove Variant-Level Artifacts in Alzheimer Disease Sequencing Project Data

Neurology Genetics, Aug 11, 2022

Background and ObjectivesExome sequencing (ES) and genome sequencing (GS) are expected to be crit... more Background and ObjectivesExome sequencing (ES) and genome sequencing (GS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer Disease Sequencing Project (ADSP) has taken a leading role in sequencing AD-related samples at scale, with the resultant data being made publicly available to researchers to generate new insights into the genetic etiology of AD. To achieve sufficient power, the ADSP has adapted a study design where subsets of larger AD cohorts are collected and sequenced across multiple centers, using a variety of sequencing platforms. This approach may lead to variable variant quality across sequencing centers and/or platforms. In this study, we sought to implement and evaluate filters that can be applied fast to robustly remove variant-level artifacts in the ADSP data.MethodsWe implemented a robust quality control procedure to handle ADSP data. We evaluated this procedure while performing exome-wide and genome-wide association analyses on AD risk using the latest ADSP whole ES (WES) and whole GS (WGS) data releases (NG00067.v5).ResultsWe observed that many variants displayed large variation in allele frequencies across sequencing centers/platforms and contributed to spurious association signals with AD risk. We also observed that sequencing platform/center adjustment in association models could not fully account for these spurious signals. To address this issue, we designed and implemented variant filters that could capture and remove these center-specific/platform-specific artifactual variants.DiscussionWe derived a fast and robust approach to filter variants that represent sequencing center-related or platform-related artifacts underlying spurious associations with AD risk in ADSP WES and WGS data. This approach will be important to support future robust genetic association studies on ADSP data, as well as other studies with similar designs.

Single dose bioavailability and pharmacokinetic study of a innovative formulation of α-lipoic acid (ALA600) in healthy volunteers

PubMed, Dec 1, 2011

Aim: α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxid... more Aim: α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxidant properties. The present study was aimed to examine the human bioavailability, pharmacokinetics (PK) and tolerability of an innovative oral formulation (ALA600) containing racemic α-lipoic acid 600 mg. Methods: After a single 600-mg oral administration in healthy volunteers, blood samples were collected up to 8 hours post dosing, and plasma α-lipoic acid concentrations were determined by Liquid Chromatography-Mass Spectrometry (LC-MS) detection. Results: The PK data revealed a short time to reach plasma peak oncentrations (50.8± 4.2 min) with a C(max) of 6.86±1.29 µg/mL. The C(max) implying that the new pharmaceutical form positively influences absorption and absorption time. The AUC value of 5.65±0.79 µg/mL*h is the more reliable measure of new formulation bioavailability. The half-life and MRT values further show that new formulation is absorbed consistently and rapidly and is eliminated efficiently. These PK data appear to promote further refinement of present formulation. Should the authors compare the obtained data with the recent published data, the new formulation of α-lipoic acid tends to show an improvement of C(max) value (2.5-5.4 times) and AUC (1.8 times). Conclusion: ALA600 formulation is characterized by rapid absorption, high bioavailability, brief half-life and low toxicity. These PK parameters could significantly increase clinical use of lipoic acid with improvement of the therapeutic effects at the cellular level and might also prove to be the most suitable formulation for chronic administration such as peripheral neuropathies.

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Neurobiology of Aging, May 1, 2021

PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions

Molecular Cell, Mar 1, 2018

P1‐138: X CHROMOSOME GENE <i>MTM1</i> IS IMPLICATED IN BRAIN BETA‐AMYLOID ACCUMULATION

Alzheimers & Dementia, Jul 1, 2018

Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta... more Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta-amyloid accumulation. A. Mean annual percent 18 Leigh Christopher, Grace Tam, Valerio Napolioni, Yongha Kim, Michael D. Greicius, Stanford University, Stanford, CA, USA. Contact e-mail: [email protected] change in [ F] AV45 in males according to genotype demonstrating reduced beta-amyloid accumulation in the G genotype. B. Mean annual percent change in [F] AV45 in females demonstrating reduced beta-amyloid accumulation with increasing G allele dosage. Background:Brain beta-amyloid accumulation is a hallmark characteristic of Alzheimer’s disease (AD); however, it is unknown whether common genetic variation on the X-Chromosome plays a role. Thus, we performed an X Chromosome-Wide Association Study (XWAS) to discover single nucleotide polymorphisms (SNPs) associated with longitudinal accumulation of beta-amyloid in the brain as a proxy for disease progression. Methods: Participants were part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n1⁄4 621). [F] AV45 PET scans were acquired and pre-processed. [F] AV45 is a radiotracer that binds to beta-amyloid plaques. Genotype data underwent standard quality control and were imputed. XWAS 2.0 was used to run a sex-stratified test (analyzed according to Stouffer’s method) with mean annual percent change in global [F] AV45 (cerebellum normalized) as the quantitative trait. We then tested whether significant variants associated with 1) baseline CSF tau levels 2) longitudinal change in cognitive performance (memory, language and global cognition) using a linear mixed effects model in an independent dataset. Results:A variant upstream of the geneMTM1, rs11094635, was significantly associated with beta-amyloid accumulation (Figure 1, rs11094635 C/G, MAF1⁄4 0.30, Stouffers Z 1⁄4 -4.81, p 1⁄4 1.5 x 10). The minor allele (G) demonstrated a protective effect on beta-amyloid accumulation (Figure 2). Dosage of the minor allele was also associated with lower baseline CSF tau levels (p< 0.05) and a less rapid decline on Boston Naming Task scores in individuals who converted to AD (p1⁄40.012). As a post-hoc analysis, we ran a gene-based test for both beta-amyloid accumulation and AD risk (in a separate case control dataset) to see whether overlapping genes contribute

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Neuron, Mar 1, 2019

GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals

Alzheimers & Dementia, Dec 1, 2022

Genetic adaptation to historical pathogen burdens

Infection, Genetics and Evolution, Oct 1, 2017

The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates

Journal of Psychiatric Research, Dec 1, 2014

Autism genetics

Behavioural Brain Research, Aug 1, 2013

Selection, Identification and Functional Performance of Ammonia-Degrading Microbial Communities from an Activated Sludge for Landfill Leachate Treatment

Microorganisms, Jan 25, 2023

The ARES Project: Cloud Services for Medical Genomics

Urinary p-cresol in autism spectrum disorder

Neurotoxicology and Teratology, Mar 1, 2013

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood a... more Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children.

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: Association and gene–gene interaction study in a population of Central Italy

Neuroscience Letters, Aug 1, 2012

A fast and robust strategy to remove variant level artifacts in Alzheimer’s Disease Sequencing Project data

medRxiv (Cold Spring Harbor Laboratory), Oct 30, 2021

APOE missense variant R145C is associated with increased Alzheimer's disease risk in African ancestry individuals with the APOE ϵ3/ϵ4 genotype

medRxiv (Cold Spring Harbor Laboratory), Oct 26, 2021

<i>CDA</i> gene polymorphisms and enzyme activity: genotype–phenotype relationship in an Italian–Caucasian population

Pharmacogenomics, May 1, 2013

Genome-wide expression of the residual lung reacting to experimental Pneumonectomy

BMC Genomics, Dec 6, 2021

Dog–human translational genomics: state of the art and genomic resources

Journal of Applied Genetics, Sep 8, 2022

PERHAPS: Paired-End short Reads-based HAPlotyping from next-generation Sequencing data

Briefings in Bioinformatics, Dec 8, 2020

The identification of rare haplotypes may greatly expand our knowledge in the genetic architectur... more The identification of rare haplotypes may greatly expand our knowledge in the genetic architecture of both complex and monogenic traits. To this aim, we developed PERHAPS (Paired-End short Reads-based HAPlotyping from next-generation Sequencing data), a new and simple approach to directly call haplotypes from short-read, paired-end Next Generation Sequencing (NGS) data. To benchmark this method, we considered the APOE classic polymorphism (*1/*2/*3/*4), since it represents one of the best examples of functional polymorphism arising from the haplotype combination of two Single Nucleotide Polymorphisms (SNPs). We leveraged the big Whole Exome Sequencing (WES) and SNP-array data obtained from the multi-ethnic UK BioBank (UKBB, N=48,855). By applying PERHAPS, based on piecing together the paired-end reads according to their FASTQ-labels, we extracted the haplotype data, along with their frequencies and the individual diplotype. Concordance rates between WES directly called diplotypes and the ones generated through statistical pre-phasing and imputation of SNP-array data are extremely high (&gt;99%), either when stratifying the sample by SNP-array genotyping batch or self-reported ethnic group. Hardy-Weinberg Equilibrium tests and the comparison of obtained haplotype frequencies with the ones available from the 1000 Genome Project further supported the reliability of PERHAPS. Notably, we were able to determine the existence of the rare APOE*1 haplotype in two unrelated African subjects from UKBB, supporting its presence at appreciable frequency (approximatively 0.5%) in the African Yoruba population. Despite acknowledging some technical shortcomings, PERHAPS represents a novel and simple approach that will partly overcome the limitations in direct haplotype calling from short read-based sequencing.

A Fast and Robust Strategy to Remove Variant-Level Artifacts in Alzheimer Disease Sequencing Project Data

Neurology Genetics, Aug 11, 2022

Background and ObjectivesExome sequencing (ES) and genome sequencing (GS) are expected to be crit... more Background and ObjectivesExome sequencing (ES) and genome sequencing (GS) are expected to be critical to further elucidate the missing genetic heritability of Alzheimer disease (AD) risk by identifying rare coding and/or noncoding variants that contribute to AD pathogenesis. In the United States, the Alzheimer Disease Sequencing Project (ADSP) has taken a leading role in sequencing AD-related samples at scale, with the resultant data being made publicly available to researchers to generate new insights into the genetic etiology of AD. To achieve sufficient power, the ADSP has adapted a study design where subsets of larger AD cohorts are collected and sequenced across multiple centers, using a variety of sequencing platforms. This approach may lead to variable variant quality across sequencing centers and/or platforms. In this study, we sought to implement and evaluate filters that can be applied fast to robustly remove variant-level artifacts in the ADSP data.MethodsWe implemented a robust quality control procedure to handle ADSP data. We evaluated this procedure while performing exome-wide and genome-wide association analyses on AD risk using the latest ADSP whole ES (WES) and whole GS (WGS) data releases (NG00067.v5).ResultsWe observed that many variants displayed large variation in allele frequencies across sequencing centers/platforms and contributed to spurious association signals with AD risk. We also observed that sequencing platform/center adjustment in association models could not fully account for these spurious signals. To address this issue, we designed and implemented variant filters that could capture and remove these center-specific/platform-specific artifactual variants.DiscussionWe derived a fast and robust approach to filter variants that represent sequencing center-related or platform-related artifacts underlying spurious associations with AD risk in ADSP WES and WGS data. This approach will be important to support future robust genetic association studies on ADSP data, as well as other studies with similar designs.

Single dose bioavailability and pharmacokinetic study of a innovative formulation of α-lipoic acid (ALA600) in healthy volunteers

PubMed, Dec 1, 2011

Aim: α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxid... more Aim: α-Lipoic acid is an important micronutrient with several pharmacological as well as antioxidant properties. The present study was aimed to examine the human bioavailability, pharmacokinetics (PK) and tolerability of an innovative oral formulation (ALA600) containing racemic α-lipoic acid 600 mg. Methods: After a single 600-mg oral administration in healthy volunteers, blood samples were collected up to 8 hours post dosing, and plasma α-lipoic acid concentrations were determined by Liquid Chromatography-Mass Spectrometry (LC-MS) detection. Results: The PK data revealed a short time to reach plasma peak oncentrations (50.8± 4.2 min) with a C(max) of 6.86±1.29 µg/mL. The C(max) implying that the new pharmaceutical form positively influences absorption and absorption time. The AUC value of 5.65±0.79 µg/mL*h is the more reliable measure of new formulation bioavailability. The half-life and MRT values further show that new formulation is absorbed consistently and rapidly and is eliminated efficiently. These PK data appear to promote further refinement of present formulation. Should the authors compare the obtained data with the recent published data, the new formulation of α-lipoic acid tends to show an improvement of C(max) value (2.5-5.4 times) and AUC (1.8 times). Conclusion: ALA600 formulation is characterized by rapid absorption, high bioavailability, brief half-life and low toxicity. These PK parameters could significantly increase clinical use of lipoic acid with improvement of the therapeutic effects at the cellular level and might also prove to be the most suitable formulation for chronic administration such as peripheral neuropathies.

KL∗VS heterozygosity reduces brain amyloid in asymptomatic at-risk APOE∗4 carriers

Neurobiology of Aging, May 1, 2021

PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions

Molecular Cell, Mar 1, 2018

P1‐138: X CHROMOSOME GENE <i>MTM1</i> IS IMPLICATED IN BRAIN BETA‐AMYLOID ACCUMULATION

Alzheimers & Dementia, Jul 1, 2018

Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta... more Figure 2. X Chromosome variant rs11094635-G demonstrates a protective effect on longitudinal beta-amyloid accumulation. A. Mean annual percent 18 Leigh Christopher, Grace Tam, Valerio Napolioni, Yongha Kim, Michael D. Greicius, Stanford University, Stanford, CA, USA. Contact e-mail: [email protected] change in [ F] AV45 in males according to genotype demonstrating reduced beta-amyloid accumulation in the G genotype. B. Mean annual percent change in [F] AV45 in females demonstrating reduced beta-amyloid accumulation with increasing G allele dosage. Background:Brain beta-amyloid accumulation is a hallmark characteristic of Alzheimer’s disease (AD); however, it is unknown whether common genetic variation on the X-Chromosome plays a role. Thus, we performed an X Chromosome-Wide Association Study (XWAS) to discover single nucleotide polymorphisms (SNPs) associated with longitudinal accumulation of beta-amyloid in the brain as a proxy for disease progression. Methods: Participants were part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI, n1⁄4 621). [F] AV45 PET scans were acquired and pre-processed. [F] AV45 is a radiotracer that binds to beta-amyloid plaques. Genotype data underwent standard quality control and were imputed. XWAS 2.0 was used to run a sex-stratified test (analyzed according to Stouffer’s method) with mean annual percent change in global [F] AV45 (cerebellum normalized) as the quantitative trait. We then tested whether significant variants associated with 1) baseline CSF tau levels 2) longitudinal change in cognitive performance (memory, language and global cognition) using a linear mixed effects model in an independent dataset. Results:A variant upstream of the geneMTM1, rs11094635, was significantly associated with beta-amyloid accumulation (Figure 1, rs11094635 C/G, MAF1⁄4 0.30, Stouffers Z 1⁄4 -4.81, p 1⁄4 1.5 x 10). The minor allele (G) demonstrated a protective effect on beta-amyloid accumulation (Figure 2). Dosage of the minor allele was also associated with lower baseline CSF tau levels (p< 0.05) and a less rapid decline on Boston Naming Task scores in individuals who converted to AD (p1⁄40.012). As a post-hoc analysis, we ran a gene-based test for both beta-amyloid accumulation and AD risk (in a separate case control dataset) to see whether overlapping genes contribute

A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Neuron, Mar 1, 2019

GWAS of Genetic Resilience to Age‐Related Risk for Alzheimer’s Disease in Admixed African Ancestry Individuals

Alzheimers & Dementia, Dec 1, 2022

Genetic adaptation to historical pathogen burdens

Infection, Genetics and Evolution, Oct 1, 2017

The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates

Journal of Psychiatric Research, Dec 1, 2014

Autism genetics

Behavioural Brain Research, Aug 1, 2013

Selection, Identification and Functional Performance of Ammonia-Degrading Microbial Communities from an Activated Sludge for Landfill Leachate Treatment

Microorganisms, Jan 25, 2023

The ARES Project: Cloud Services for Medical Genomics

Urinary p-cresol in autism spectrum disorder

Neurotoxicology and Teratology, Mar 1, 2013

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood a... more Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children.

DRD2/ANKK1 TaqIA and SLC6A3 VNTR polymorphisms in alcohol dependence: Association and gene–gene interaction study in a population of Central Italy

Neuroscience Letters, Aug 1, 2012

A fast and robust strategy to remove variant level artifacts in Alzheimer’s Disease Sequencing Project data

medRxiv (Cold Spring Harbor Laboratory), Oct 30, 2021

APOE missense variant R145C is associated with increased Alzheimer's disease risk in African ancestry individuals with the APOE ϵ3/ϵ4 genotype

medRxiv (Cold Spring Harbor Laboratory), Oct 26, 2021

<i>CDA</i> gene polymorphisms and enzyme activity: genotype–phenotype relationship in an Italian–Caucasian population

Pharmacogenomics, May 1, 2013