Publications by authors named "Alison M Goate"

216 Publications

Current directions in tau research: Highlights from Tau 2020.

Alzheimers Dement 2021 Sep 28. Epub 2021 Sep 28.

Neurodegeneration Development Unit, Biogen, Boston, Massachusetts, USA.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.
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http://dx.doi.org/10.1002/alz.12452DOI Listing
September 2021

Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques.

Mol Neurodegener 2021 Sep 25;16(1):68. Epub 2021 Sep 25.

VIB Center for Brain & Disease Research, Leuven, Belgium.

Background: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.

Results: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background.

Conclusions: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.
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http://dx.doi.org/10.1186/s13024-021-00487-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467145PMC
September 2021

Polygenic score modifies risk for Alzheimer's disease in ε4 homozygotes at phenotypic extremes.

Alzheimers Dement (Amst) 2021 5;13(1):e12226. Epub 2021 Aug 5.

Department of Epidemiology and Preventive Medicine School of Public Health and Preventive Medicine Monash University Melbourne Australia.

Introduction: Diversity in cognition among apolipoprotein E () ε4 homozygotes can range from early-onset Alzheimer's disease (AD) to a lifetime with no symptoms.

Methods: We evaluated a phenotypic extreme polygenic risk score (PRS) for AD between cognitively healthy ε4 homozygotes aged ≥75 years (n = 213) and early-onset ε4 homozygote AD cases aged ≤65 years (n = 223) as an explanation for this diversity.

Results: The PRS for AD was significantly higher in ε4 homozygote AD cases compared to older cognitively healthy ε4/ε4 controls (odds ratio [OR] 8.39; confidence interval [CI] 2.0-35.2;  = .003). The difference in the same PRS between ε3/ε3 extremes was not as significant (OR 3.13; CI 0.98-9.92;  = .053) despite similar numbers and power. There was no statistical difference in an educational attainment PRS between these age extreme case-controls.

Discussion: A PRS for AD contributes to modified cognitive expression of the ε4/ε4 genotype at phenotypic extremes of risk.
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http://dx.doi.org/10.1002/dad2.12226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339682PMC
August 2021

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids.

Cell 2021 Aug 26;184(17):4547-4563.e17. Epub 2021 Jul 26.

Neural Stem Cell Institute, Rensselaer, NY 12144, USA. Electronic address:

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.
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http://dx.doi.org/10.1016/j.cell.2021.07.003DOI Listing
August 2021

Heterogeneous effects of genetic risk for Alzheimer's disease on the phenome.

Transl Psychiatry 2021 07 23;11(1):406. Epub 2021 Jul 23.

Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA.

Here we report how four major forms of Alzheimer's disease (AD) genetic risk-APOE-ε4, APOE-ε2, polygenic risk and familial risk-are associated with 273 traits in ~500,000 individuals in the UK Biobank. The traits cover blood biochemistry and cell traits, metabolic and general health, psychosocial health, and cognitive function. The difference in the profile of traits associated with the different forms of AD risk is striking and may contribute to heterogenous presentation of the disease. However, we also identify traits significantly associated with multiple forms of AD genetic risk, as well as traits showing significant changes across ages in those at high risk of AD, which may point to their potential roles in AD etiology. Finally, we highlight how survivor effects, in particular those relating to shared risks of cardiovascular disease and AD, can generate associations that may mislead interpretation in epidemiological AD studies. The UK Biobank provides a unique opportunity to powerfully compare the effects of different forms of AD genetic risk on the phenome in the same cohort.
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http://dx.doi.org/10.1038/s41398-021-01518-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302633PMC
July 2021

Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder.

Psychol Med 2021 Jul 7:1-9. Epub 2021 Jul 7.

Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, USA.

Background: Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.

Methods: We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.

Results: We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001).

Conclusions: Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.
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http://dx.doi.org/10.1017/S003329172100266XDOI Listing
July 2021

Generation of a gene-corrected human isogenic iPSC line from an Alzheimer's disease iPSC line carrying the London mutation in APP (V717I).

Stem Cell Res 2021 05 30;53:102373. Epub 2021 Apr 30.

Department of Anatomy and Physiology, the University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, Royal Melbourne Hospital, the University of Melbourne, Parkville, VIC 3010, Australia. Electronic address:

We report the genome-editing of an existing iPSC line carrying the London mutation in APP (V717I) into an iPSC line in which the pathogenic mutation was corrected. The resulting isogenic iPSC line maintained pluripotent stem cell morphology, a normal karyotype, expression of pluripotency markers and the ability to differentiate into the three germ-layers in vitro.
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http://dx.doi.org/10.1016/j.scr.2021.102373DOI Listing
May 2021

Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population.

Aging Cell 2021 06 26;20(6):e13384. Epub 2021 May 26.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Vic, Australia.

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence for all-cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants. During a median 4.5 years of follow-up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased dementia risk and 1.4/1.8-fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4-fold dementia risk versus low (CI 1.04-1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96-1.22, p = 0.18). Incidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.
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http://dx.doi.org/10.1111/acel.13384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208779PMC
June 2021

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice.

Nat Commun 2021 04 14;12(1):2238. Epub 2021 Apr 14.

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
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http://dx.doi.org/10.1038/s41467-021-22501-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047017PMC
April 2021

Integration of Alzheimer's disease genetics and myeloid genomics identifies disease risk regulatory elements and genes.

Nat Commun 2021 03 12;12(1):1610. Epub 2021 Mar 12.

Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Genome-wide association studies (GWAS) have identified more than 40 loci associated with Alzheimer's disease (AD), but the causal variants, regulatory elements, genes and pathways remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Previously, we showed that AD risk alleles are enriched in myeloid-specific epigenomic annotations. Here, we show that they are specifically enriched in active enhancers of monocytes, macrophages and microglia. We integrated AD GWAS with myeloid epigenomic and transcriptomic datasets using analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification. We identify AD risk enhancers and nominate candidate causal genes among their likely targets (including AP4E1, AP4M1, APBB3, BIN1, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, TP53INP1, and ZYX) in twenty loci. Fine-mapping of these enhancers nominates candidate functional variants that likely modify AD risk by regulating gene expression in myeloid cells. In the MS4A locus we identified a single candidate functional variant and validated it in human induced pluripotent stem cell (hiPSC)-derived microglia and brain. Taken together, this study integrates AD GWAS with multiple myeloid genomic datasets to investigate the mechanisms of AD risk alleles and nominates candidate functional variants, regulatory elements and genes that likely modulate disease susceptibility.
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http://dx.doi.org/10.1038/s41467-021-21823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955030PMC
March 2021

Alzheimer's-associated PU.1 expression levels regulate microglial inflammatory response.

Neurobiol Dis 2021 01 8;148:105217. Epub 2020 Dec 8.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Ronald M. Loeb Center for Alzheimer's disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

More than forty loci contribute to genetic risk for Alzheimer's disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
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http://dx.doi.org/10.1016/j.nbd.2020.105217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808757PMC
January 2021

Greater effect of polygenic risk score for Alzheimer's disease among younger cases who are apolipoprotein E-ε4 carriers.

Neurobiol Aging 2021 03 30;99:101.e1-101.e9. Epub 2020 Sep 30.

Litwin-Zucker Center for Alzheimer's Disease, The Feinstein Institutes for Medical Research, Manhasset, NY, USA; Division of Geriatric Psychiatry, Zucker Hillside Hospital, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. Electronic address:

To evaluate how age and apolipoprotein E-ε4 (APOE4) status interact with APOE-independent polygenic risk score (PRS), we estimated PRS in superagers (age ≥ 90 years, N = 346), 89- controls (age 60-89, N = 2930), and Alzheimer's disease (AD) cases (N = 1760). Using superagers, we see a nearly 5 times greater odds ratio (OR) for AD comparing the top PRS decile to the lowest decile (OR = 4.82, p = 2.5 × 10), which is twice the OR as using 89- controls (OR = 2.38, p = 4.6 × 10). Thus PRS is correlated with age, which in turn is associated with APOE. Further exploring these relationships, we find that PRS modifies age at onset among APOE4 carriers, but not among noncarriers. More specifically, PRS in the top decile predicts an age at onset 5 years earlier compared with the lowest decile (70.1 vs. 75.0 years; t-test p = 2.4 × 10) among APOE4 carriers. This disproportionally large PRS among younger APOE4-positive cases is reflected in a significant statistical interaction between APOE4 status and age at onset (β = -0.02, p = 4.8 × 10) as a predictor of PRS. Thus, the known AD risk variants are particularly detrimental in young APOE4 carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559723PMC
March 2021

Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer's Disease Genetics.

Trends Neurosci 2020 12 27;43(12):965-979. Epub 2020 Oct 27.

Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and variants remain unidentified in most loci. Integration of GWAS signals with epigenomic annotations has demonstrated that AD risk variants are enriched in myeloid-specific enhancers, implicating myeloid cells in AD etiology. AD risk variants in these regulatory elements modify disease susceptibility by regulating the expression of genes that play crucial roles in microglial phagocytosis. Several of these AD risk genes are specifically expressed in myeloid cells, whereas others are ubiquitously expressed but are regulated by AD risk variants within myeloid enhancers in a cell type-specific manner. We discuss the impact of established AD risk variants on microglial phagocytosis and debris processing via the endolysosomal system.
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http://dx.doi.org/10.1016/j.tins.2020.10.002DOI Listing
December 2020

A large-scale genome-wide association study meta-analysis of cannabis use disorder.

Lancet Psychiatry 2020 12 20;7(12):1032-1045. Epub 2020 Oct 20.

Stanford University Graduate School of Education, Stanford University, Stanford, CA, USA.

Background: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder.

Methods: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations.

Findings: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86-0·93, p=6·46 × 10). Cannabis use disorder and cannabis use were genetically correlated (r 0·50, p=1·50 × 10), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia.

Interpretation: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder.

Funding: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.
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http://dx.doi.org/10.1016/S2215-0366(20)30339-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674631PMC
December 2020

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 01;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

Causal Associations Between Modifiable Risk Factors and the Alzheimer's Phenome.

Ann Neurol 2021 01 15;89(1):54-65. Epub 2020 Oct 15.

'Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Objective: The purpose of this study was to infer causal relationships between 22 previously reported risk factors for Alzheimer's disease (AD) and the "AD phenome": AD, AD age of onset (AAOS), hippocampal volume, cortical surface area and thickness, cerebrospinal fluid (CSF) levels of amyloid-β (Aβ ), tau, and ptau , and the neuropathological burden of neuritic plaques, neurofibrillary tangles (NFTs), and vascular brain injury (VBI).

Methods: Polygenic risk scores (PRS) for the 22 risk factors were computed in 26,431 AD cases/controls and the association with AD was evaluated using logistic regression. Two-sample Mendelian randomization (MR) was used to infer the causal effect of risk factors on the AD phenome.

Results: PRS for increased education and diastolic blood pressure were associated with reduced risk for AD. MR indicated that only education was causally associated with reduced risk of AD, delayed AAOS, and increased cortical surface area and thickness. Total- and LDL-cholesterol levels were causally associated with increased neuritic plaque burden, although the effects were driven by single nucleotide polymorphisms (SNPs) within the APOE locus. Diastolic blood pressure and pulse pressure are causally associated with increased risk of VBI. Furthermore, total cholesterol was associated with decreased hippocampal volume; smoking initiation with decreased cortical thickness; type 2 diabetes with an earlier AAOS; and sleep duration with increased cortical thickness.

Interpretation: Our comprehensive examination of the genetic evidence for the causal relationships between previously reported risk factors in AD using PRS and MR supports a causal role for education, blood pressure, cholesterol levels, smoking, and diabetes with the AD phenome. ANN NEUROL 2021;89:54-65.
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http://dx.doi.org/10.1002/ana.25918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088901PMC
January 2021

Risk prediction of late-onset Alzheimer's disease implies an oligogenic architecture.

Nat Commun 2020 09 23;11(1):4799. Epub 2020 Sep 23.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, 4072, Australia.

Genetic association studies have identified 44 common genome-wide significant risk loci for late-onset Alzheimer's disease (LOAD). However, LOAD genetic architecture and prediction are unclear. Here we estimate the optimal P-threshold (P) of a genetic risk score (GRS) for prediction of LOAD in three independent datasets comprising 676 cases and 35,675 family history proxy cases. We show that the discriminative ability of GRS in LOAD prediction is maximised when selecting a small number of SNPs. Both simulation results and direct estimation indicate that the number of causal common SNPs for LOAD may be less than 100, suggesting LOAD is more oligogenic than polygenic. The best GRS explains approximately 75% of SNP-heritability, and individuals in the top decile of GRS have ten-fold increased odds when compared to those in the bottom decile. In addition, 14 variants are identified that contribute to both LOAD risk and age at onset of LOAD.
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http://dx.doi.org/10.1038/s41467-020-18534-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511365PMC
September 2020

A quantitative trait rare variant nonparametric linkage method with application to age-at-onset of Alzheimer's disease.

Eur J Hum Genet 2020 12 1;28(12):1734-1742. Epub 2020 Aug 1.

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

To analyze pedigrees with quantitative trait (QT) and sequence data, we developed a rare variant (RV) quantitative nonparametric linkage (QNPL) method, which evaluates sharing of minor alleles. RV-QNPL has greater power than the traditional QNPL that tests for excess sharing of minor and major alleles. RV-QNPL is robust to population substructure and admixture, locus heterogeneity, and inclusion of nonpathogenic variants and can be readily applied outside of coding regions. When QNPL was used to analyze common variants, it often led to loci mapping to large intervals, e.g., >40 Mb. In contrast, when RVs are analyzed, regions are well defined, e.g., a gene. Using simulation studies, we demonstrate that RV-QNPL is substantially more powerful than applying traditional QNPL methods to analyze RVs. RV-QNPL was also applied to analyze age-at-onset (AAO) data for 107 late-onset Alzheimer's disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with whole-genome sequence data. When AAO of AD was analyzed regardless of APOE ε4 status, suggestive linkage (LOD = 2.4) was observed with RVs in KNDC1 and nominally significant linkage (p < 0.05) was observed with RVs in LOAD genes ABCA7 and IQCK. When AAO of AD was analyzed for APOE ε4 positive family members, nominally significant linkage was observed with RVs in APOE, while when AAO of AD was analyzed for APOE ε4 negative family members, nominal significance was observed for IQCK and ADAMTS1. RV-QNPL provides a powerful resource to analyze QTs in families to elucidate their genetic etiology.
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http://dx.doi.org/10.1038/s41431-020-0703-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785016PMC
December 2020

Genetic architecture of Alzheimer's disease.

Neurobiol Dis 2020 09 18;143:104976. Epub 2020 Jun 18.

Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA. Electronic address:

Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.
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http://dx.doi.org/10.1016/j.nbd.2020.104976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409822PMC
September 2020

A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease.

Nat Med 2020 03 11;26(3):398-407. Epub 2020 Mar 11.

Dementia Research Centre, Institute of Neurology, University College London, London, UK.

Development of tau-based therapies for Alzheimer's disease requires an understanding of the timing of disease-related changes in tau. We quantified the phosphorylation state at multiple sites of the tau protein in cerebrospinal fluid markers across four decades of disease progression in dominantly inherited Alzheimer's disease. We identified a pattern of tau staging where site-specific phosphorylation changes occur at different periods of disease progression and follow distinct trajectories over time. These tau phosphorylation state changes are uniquely associated with structural, metabolic, neurodegenerative and clinical markers of disease, and some (p-tau217 and p-tau181) begin with the initial increases in aggregate amyloid-β as early as two decades before the development of aggregated tau pathology. Others (p-tau205 and t-tau) increase with atrophy and hypometabolism closer to symptom onset. These findings provide insights into the pathways linking tau, amyloid-β and neurodegeneration, and may facilitate clinical trials of tau-based treatments.
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http://dx.doi.org/10.1038/s41591-020-0781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309367PMC
March 2020

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium.

Mol Psychiatry 2020 08 26;25(8):1673-1687. Epub 2020 Feb 26.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.
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http://dx.doi.org/10.1038/s41380-020-0677-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392789PMC
August 2020

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2.

Neurobiol Dis 2020 06 19;139:104817. Epub 2020 Feb 19.

Department of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, USA. Electronic address:

Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials.
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http://dx.doi.org/10.1016/j.nbd.2020.104817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236786PMC
June 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Novel presenilin 1 and 2 double knock-out cell line for in vitro validation of PSEN1 and PSEN2 mutations.

Neurobiol Dis 2020 05 4;138:104785. Epub 2020 Feb 4.

Ronald M. Loeb Center for Alzheimer's disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease (autosomal dominant AD or ADAD). These genes affect γ-secretase-dependent generation of Amyloid β (Aβ) peptides, the main constituent of amyloid plaques and one of the pathological hallmarks of AD. Evaluation of patients with ADAD includes assessment of family history, clinical presentation, biomarkers, neuropathology when available and DNA sequencing data. These analyses frequently uncover novel variants of unknown significance in ADAD genes. This presents a barrier to recruitment of such individuals into clinical trials, unless a biochemical test can demonstrate that a novel mutation results in altered APP processing in a manner consistent with pathogenicity. Here we describe generation and characterization of a novel presenilin 1 and 2 double knock-out in N2A mouse neuroblastoma cells using CRISPR/Cas9, which results in complete ablation of Aβ production, decreased Pen-2 expression and Nicastrin glycosylation. Because of the absence of background Aβ secretion from endogenous γ-secretases, these cells can be used for validation of PSEN1 and PSEN2 variant effects on production of Aβ or other γ-secretase substrates and for biochemical studies of γ-secretase function using novel variants. We examined several PSEN1 and PSEN2 mutations of known and unknown pathogenicity. Known mutants increased Aβ42/Aβ40 ratio with varying effect on Aβ40, Aβ42, total Aβ levels and Pen-2 expression, which aligns with previous work on these mutants. Our data on novel PSEN1 V142F, G206V and G206D mutations suggest that these mutations underlie the reported clinical observations in ADAD patients. We believe our novel cell line will be valuable for the scientific community for reliable validation of presenilin mutations and helpful in defining their pathogenicity to improve and facilitate evaluation of ADAD patients, particularly in the context of enrollment in clinical trials.
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http://dx.doi.org/10.1016/j.nbd.2020.104785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515654PMC
May 2020

Empirical design of a variant quality control pipeline for whole genome sequencing data using replicate discordance.

Sci Rep 2019 11 6;9(1):16156. Epub 2019 Nov 6.

Litwin-Zucker Center for Alzheimer's Disease, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, 11030, USA.

The success of next-generation sequencing depends on the accuracy of variant calls. Few objective protocols exist for QC following variant calling from whole genome sequencing (WGS) data. After applying QC filtering based on Genome Analysis Tool Kit (GATK) best practices, we used genotype discordance of eight samples that were sequenced twice each to evaluate the proportion of potentially inaccurate variant calls. We designed a QC pipeline involving hard filters to improve replicate genotype concordance, which indicates improved accuracy of genotype calls. Our pipeline analyzes the efficacy of each filtering step. We initially applied this strategy to well-characterized variants from the ClinVar database, and subsequently to the full WGS dataset. The genome-wide biallelic pipeline removed 82.11% of discordant and 14.89% of concordant genotypes, and improved the concordance rate from 98.53% to 99.69%. The variant-level read depth filter most improved the genome-wide biallelic concordance rate. We also adapted this pipeline for triallelic sites, given the increasing proportion of multiallelic sites as sample sizes increase. For triallelic sites containing only SNVs, the concordance rate improved from 97.68% to 99.80%. Our QC pipeline removes many potentially false positive calls that pass in GATK, and may inform future WGS studies prior to variant effect analysis.
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http://dx.doi.org/10.1038/s41598-019-52614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834861PMC
November 2019

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Stem Cell Reports 2019 11 17;13(5):939-955. Epub 2019 Oct 17.

Department of Molecular Cellular and Developmental Biology, Neuroscience Research Institute, Biomolecular Science and Engineering Program, University of California, Santa Barbara, Santa Barbara, CA, USA.

Primary tauopathies are characterized neuropathologically by inclusions containing abnormal forms of the microtubule-associated protein tau (MAPT) and clinically by diverse neuropsychiatric, cognitive, and motor impairments. Autosomal dominant mutations in the MAPT gene cause heterogeneous forms of frontotemporal lobar degeneration with tauopathy (FTLD-Tau). Common and rare variants in the MAPT gene increase the risk for sporadic FTLD-Tau, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We generated a collection of fibroblasts from 140 MAPT mutation/risk variant carriers, PSP, CBD, and cognitively normal controls; 31 induced pluripotent stem cell (iPSC) lines from MAPT mutation carriers, non-carrier family members, and autopsy-confirmed PSP patients; 33 genome engineered iPSCs that were corrected or mutagenized; and forebrain neural progenitor cells (NPCs). Here, we present a resource of fibroblasts, iPSCs, and NPCs with comprehensive clinical histories that can be accessed by the scientific community for disease modeling and development of novel therapeutics for tauopathies.
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http://dx.doi.org/10.1016/j.stemcr.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895712PMC
November 2019

A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

Am J Hum Genet 2019 10;105(4):822-835

Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Taub Institute on Alzheimer Disease and the Aging Brain, and Gertrude H. Sergievsky Center, Columbia University, New York, NY 10027, USA; Center for Statistical Genetics, Columbia University, New York, NY 10027, USA. Electronic address:

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817540PMC
October 2019

Sex differences in the genetic predictors of Alzheimer's pathology.

Brain 2019 09;142(9):2581-2589

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.

Autopsy measures of Alzheimer's disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer's disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer's disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer's disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10-8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10-8) but not females (P = 0.85, sex-interaction P = 2.9 × 10-4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
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http://dx.doi.org/10.1093/brain/awz206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736148PMC
September 2019

Allele-specific expression and high-throughput reporter assay reveal functional genetic variants associated with alcohol use disorders.

Mol Psychiatry 2021 04 2;26(4):1142-1151. Epub 2019 Sep 2.

Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.

Genome-wide association studies (GWAS) of complex traits, such as alcohol use disorders (AUD), usually identify variants in non-coding regions and cannot by themselves distinguish whether the associated variants are functional or in linkage disequilibrium with the functional variants. Transcriptome studies can identify genes whose expression differs between alcoholics and controls. To test which variants associated with AUD may cause expression differences, we integrated data from deep RNA-seq and GWAS of four postmortem brain regions from 30 subjects with AUD and 30 controls to analyze allele-specific expression (ASE). We identified 88 genes with differential ASE in subjects with AUD compared to controls. Next, to test one potential mechanism contributing to the differential ASE, we analyzed single nucleotide polymorphisms (SNPs) in the 3' untranslated regions (3'UTR) of these genes. Of the 88 genes with differential ASE, 61 genes contained 437 SNPs in the 3'UTR with at least one heterozygote among the subjects studied. Using a modified PASSPORT-seq (parallel assessment of polymorphisms in miRNA target-sites by sequencing) assay, we identified 25 SNPs that affected RNA levels in a consistent manner in two neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Many of these SNPs are in binding sites of miRNAs and RNA-binding proteins, indicating that these SNPs are likely causal variants of AUD-associated differential ASE. In sum, we demonstrate that a combination of computational and experimental approaches provides a powerful strategy to uncover functionally relevant variants associated with the risk for AUD.
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http://dx.doi.org/10.1038/s41380-019-0508-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050407PMC
April 2021
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