ABSTRACT
Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.
ABSTRACT
Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases.
Subject(s)
Alzheimer Disease , Amyotrophic Lateral Sclerosis , Lewy Body Disease , Neurodegenerative Diseases , Parkinson Disease , Humans , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Lewy Body Disease/genetics , Lewy Body Disease/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Amyotrophic Lateral Sclerosis/geneticsABSTRACT
Proxy phenotypes allow for the utilization of genetic data from large population cohorts to analyze late-onset diseases by using parental diagnoses as a proxy for genetic disease risk. Proxy phenotypes based on parental diagnosis status have been used in previous studies to identify common variants associated with Alzheimer's disease. As of yet, proxy phenotypes have not been used to identify genes associated with Alzheimer's disease through rare variants. Here we show that a proxy Alzheimer's disease/dementia phenotype can capture known Alzheimer's disease risk genes through rare variant aggregation. We generated a proxy Alzheimer's disease/dementia phenotype for 148,508 unrelated individuals of European ancestry in the UK biobank in order to perform exome-wide rare variant aggregation analyses to identify genes associated with proxy Alzheimer's disease/dementia. We identified four genes significantly associated with the proxy phenotype, three of which were significantly associated with proxy Alzheimer's disease/dementia in an independent replication cohort consisting of 197,506 unrelated individuals of European ancestry in the UK biobank. All three of the replicated genes have been previously associated with clinically diagnosed Alzheimer's disease (SORL1, TREM2, and TOMM40/APOE). We show that proxy Alzheimer's disease/dementia can be used to identify genes associated with Alzheimer's disease through rare variant aggregation.
Subject(s)
Alzheimer Disease , Humans , Alzheimer Disease/genetics , Genetic Variation , Exome , Genome-Wide Association Study , Risk Factors , Genetic Predisposition to Disease , LDL-Receptor Related Proteins/genetics , Membrane Transport Proteins/geneticsABSTRACT
Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%1. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-ß precursor protein processing, amyloid-ß aggregation, lipid metabolism and microglial function in AD.
Subject(s)
ATP Binding Cassette Transporter 1 , Adenosine Triphosphatases , Alzheimer Disease , Exosomes , Humans , Adenosine Triphosphatases/genetics , Alzheimer Disease/genetics , ATP Binding Cassette Transporter 1/genetics , Genome-Wide Association Study , Risk Factors , Exosomes/geneticsABSTRACT
Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
Subject(s)
Alzheimer Disease , Alzheimer Disease/pathology , Amyloid beta-Peptides/cerebrospinal fluid , Apolipoproteins E/genetics , Biomarkers/cerebrospinal fluid , Cell Cycle Proteins , Humans , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , tau Proteins/geneticsABSTRACT
A quarter of the world's population is estimated to meet the criteria for metabolic syndrome (MetS), a cluster of cardiometabolic risk factors that promote development of coronary artery disease and type 2 diabetes, leading to increased risk of premature death and significant health costs. In this study we investigate whether the genetics associated with MetS components mirror their phenotypic clustering. A multivariate approach that leverages genetic correlations of fasting glucose, HDL cholesterol, systolic blood pressure, triglycerides, and waist circumference was used, which revealed that these genetic correlations are best captured by a genetic one factor model. The common genetic factor genome-wide association study (GWAS) detects 235 associated loci, 174 more than the largest GWAS on MetS to date. Of these loci, 53 (22.5%) overlap with loci identified for two or more MetS components, indicating that MetS is a complex, heterogeneous disorder. Associated loci harbor genes that show increased expression in the brain, especially in GABAergic and dopaminergic neurons. A polygenic risk score drafted from the MetS factor GWAS predicts 5.9% of the variance in MetS. These results provide mechanistic insights into the genetics of MetS and suggestions for drug targets, especially fenofibrate, which has the promise of tackling multiple MetS components.
Subject(s)
Diabetes Mellitus, Type 2 , Fenofibrate , Metabolic Syndrome , Humans , Metabolic Syndrome/epidemiology , Cholesterol, HDL , Genome-Wide Association Study , Diabetes Mellitus, Type 2/genetics , Risk Factors , Triglycerides , Waist Circumference , Blood Pressure , Glucose , Blood GlucoseABSTRACT
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Cognitive Dysfunction/psychology , Genome-Wide Association Study , Humans , tau Proteins/geneticsABSTRACT
BACKGROUND: Genetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE. METHODS: We used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches. RESULTS: Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost. CONCLUSIONS: We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.
Subject(s)
Alzheimer Disease , Apolipoproteins E , Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Apolipoproteins E/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans , Middle Aged , Quality ControlABSTRACT
Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8years, 41% female, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal cerebrospinal fluid (CSF) amyloid-beta status (A+/-) with cognitive decline and dementia risk. Age-, sex- and education-adjusted linear mixed models showed that compared to Met-A-, Met+A+ showed steeper decline on tests of global cognition, memory, language, attention and executive functioning, while Met-A+ showed steeper decline on a smaller number of tests. There were no associations between Met+A- and cognitive decline. Cox models showed that compared to Met-A-, Met+A+ participants were at increased risk of dementia (HR=8.8, 95%CI: 2.8-27.9), as were Met-A+ participants (HR=6.5, 95%CI: 2.2-19.5). Lower plasma BDNF was associated with an increased risk of progression to dementia in the A+ participants. Our results imply that Met-carriage on top of amyloid-beta pathology might increase rate of cognitive decline to dementia.
Subject(s)
Aging/genetics , Aging/metabolism , Amyloid beta-Peptides/cerebrospinal fluid , Brain-Derived Neurotrophic Factor/genetics , Cognition , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Polymorphism, Genetic , Aged , Aging/psychology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Brain-Derived Neurotrophic Factor/blood , Brain-Derived Neurotrophic Factor/physiology , Dementia/genetics , Dementia/metabolism , Female , Humans , Male , Middle Aged , RiskABSTRACT
Genetic factors play a major role in frontotemporal dementia (FTD). The majority of FTD cannot be genetically explained yet and it is likely that there are still FTD risk loci to be discovered. Common variants have been identified with genome-wide association studies (GWAS), but these studies have not systematically searched for rare variants. To identify rare and new common variant FTD risk loci and provide more insight into the heritability of C9ORF72-related FTD, we performed a GWAS consisting of 354 FTD patients (including and excluding N = 28 pathological repeat carriers) and 4209 control subjects. The Haplotype Reference Consortium was used as reference panel, allowing for the imputation of rare genetic variants. Two rare genetic variants nearby C9ORF72 were strongly associated with FTD in the discovery (rs147211831: OR = 4.8, P = 9.2 × 10-9, rs117204439: OR = 4.9, P = 6.0 × 10-9) and replication analysis (P < 1.1 × 10-3). These variants also significantly associated with amyotrophic lateral sclerosis in a publicly available dataset. Using haplotype analyses in 1200 individuals, we showed that these variants tag a sub-haplotype of the founder haplotype of the repeat expansion that was previously found to be present in virtually all pathological C9ORF72 G4C2 repeat lengths. This new risk haplotype was 10 times more likely to contain a C9ORF72 pathological repeat length compared to founder haplotypes without one of the two risk variants (~22% versus ~2%; P = 7.70 × 10-58). In haplotypes without a pathologic expansion, the founder risk haplotype had a higher number of repeats (median = 12 repeats) compared to the founder haplotype without the risk variants (median = 8 repeats) (P = 2.05 × 10-260). In conclusion, the identified risk haplotype, which is carried by ~4% of all individuals, is a major risk factor for pathological repeat lengths of C9ORF72 G4C2. These findings strongly indicate that longer C9ORF72 repeats are unstable and more likely to convert to germline pathological C9ORF72 repeat expansions.
Subject(s)
C9orf72 Protein/genetics , Frontotemporal Dementia , Genome-Wide Association Study , DNA Repeat Expansion/genetics , Frontotemporal Dementia/genetics , Haplotypes , HumansABSTRACT
Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Microglia/cytology , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , Proteins/metabolism , Proteolysis , Sample SizeABSTRACT
INTRODUCTION: We investigated relationships among genetic determinants of Alzheimer's disease (AD), amyloid/tau/neurodegenaration (ATN) biomarkers, and risk of dementia. METHODS: We studied cognitively normal individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort and SCIENCe project. We examined associations between genetic variants and ATN biomarkers, and evaluated their predictive value for incident dementia. A polygenic risk score (PRS) was calculated based on 39 genetic variants. The APOE gene was not included in the PRS and was analyzed separately. RESULTS: The PRS and APOE ε4 were associated with amyloid-positive ATN profiles, and APOE ε4 additionally with isolated increased tau (A-T+N-). A high PRS and APOE ε4 separately predicted AD dementia. Combined, a high PRS increased while a low PRS attenuated the risk associated with ε4 carriers. DISCUSSION: Genetic variants beyond APOE are clinically relevant and contribute to the pathophysiology of AD. In the future, a PRS might be used in individualized risk profiling.
ABSTRACT
BACKGROUND: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. OBJECTIVE: We tested if genetic variants in part explain the heterogeneity in DLB. METHODS: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aß1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. RESULTS: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE É4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE É4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. CONCLUSION: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/cerebrospinal fluid , Lewy Body Disease , Mutation/genetics , tau Proteins/cerebrospinal fluid , Aged , Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Cohort Studies , Female , Glucosylceramidase/genetics , Humans , Lewy Body Disease/diagnosis , Lewy Body Disease/genetics , Lewy Body Disease/pathology , Male , Mental Status and Dementia Tests/statistics & numerical data , Parkinson Disease/genetics , Parkinson Disease/pathologyABSTRACT
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE É4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
Subject(s)
Alzheimer Disease/genetics , Multifactorial Inheritance , Age of Onset , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Apolipoproteins E/genetics , Case-Control Studies , Cohort Studies , Datasets as Topic , Female , Follow-Up Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Heterozygote , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Assessment/methods , Risk FactorsABSTRACT
Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer's disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for ß-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.
ABSTRACT
PURPOSE: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728. METHODS: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies. RESULTS: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2. CONCLUSION: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.