The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 ...on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.
The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous ...mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H P = 9.17 × 10(-4), odds ratio (OR) = 2.63 (1.44-4.81) and p.R62H P = 2.36 × 10(-4), OR = 2.36 (1.47-3.80) were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD PSKAT-O = 5.37 × 10(-7); OR = 2.55 (1.80-3.67). The association of TREM2 variants with AD is still highly significant after excluding p.R47H PSKAT-O = 7.72 × 10(-5); OR = 2.47 (1.62-3.87), indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 × 10(-2)) and p.R62H (P = 6.87 × 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.
Cerebrospinal fluid (CSF) 42 amino acid species of amyloid beta (Aβ42) and tau levels are strongly correlated with the presence of Alzheimer's disease (AD) neuropathology including amyloid plaques ...and neurodegeneration and have been successfully used as endophenotypes for genetic studies of AD. Additional CSF analytes may also serve as useful endophenotypes that capture other aspects of AD pathophysiology. Here we have conducted a genome-wide association study of CSF levels of 59 AD-related analytes. All analytes were measured using the Rules Based Medicine Human DiscoveryMAP Panel, which includes analytes relevant to several disease-related processes. Data from two independently collected and measured datasets, the Knight Alzheimer's Disease Research Center (ADRC) and Alzheimer's Disease Neuroimaging Initiative (ADNI), were analyzed separately, and combined results were obtained using meta-analysis. We identified genetic associations with CSF levels of 5 proteins (Angiotensin-converting enzyme (ACE), Chemokine (C-C motif) ligand 2 (CCL2), Chemokine (C-C motif) ligand 4 (CCL4), Interleukin 6 receptor (IL6R) and Matrix metalloproteinase-3 (MMP3)) with study-wide significant p-values (p<1.46×10-10) and significant, consistent evidence for association in both the Knight ADRC and the ADNI samples. These proteins are involved in amyloid processing and pro-inflammatory signaling. SNPs associated with ACE, IL6R and MMP3 protein levels are located within the coding regions of the corresponding structural gene. The SNPs associated with CSF levels of CCL4 and CCL2 are located in known chemokine binding proteins. The genetic associations reported here are novel and suggest mechanisms for genetic control of CSF and plasma levels of these disease-related proteins. Significant SNPs in ACE and MMP3 also showed association with AD risk. Our findings suggest that these proteins/pathways may be valuable therapeutic targets for AD. Robust associations in cognitively normal individuals suggest that these SNPs also influence regulation of these proteins more generally and may therefore be relevant to other diseases.
Background Identification of the physiologic changes that occur during the early stages of Alzheimer’s disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of ...disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer’s Disease Research Center ( N = 311) and the Alzheimer’s Disease Neuroimaging Initiative ( N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181 ) and Aβ42 was used as a continuous trait in these analyses. Results The ptau181 -Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181 , low Aβ42 ) compared with elderly control subjects with no pathology (low ptau181 , high Aβ42 ). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181 -Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
Parkinson's disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified.
To ...better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue.
We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue.
These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.
Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent ...alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (
N
= 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case–control sample (
N
= 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (
p
= 2.1 × 10
−6
) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (
p
= 7.1 × 10
−7
), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the
LMO1
(
p
= 7.2 × 10
−7
) and
PLCL1
genes (
p
= 4.1 × 10
−6
) with maxdrinks. A variant in
AUTS2
and variants in
INADL
,
C15orf32
and
HIP1
that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (
p
≤ 10
−4
) far more showed the same direction of effect in the other dataset than would be expected by chance (
p
= 2 × 10
−3
, 3 × 10
−6
), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.
The primary constituents of plaques (Aβ42/Aβ40) and neurofibrillary tangles (tau and phosphorylated forms of tau ptau) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) ...biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Aβ42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 × 10(-4)) and ptau (p = 1.8 × 10(-3)) levels. The association of the p.E318G variant with Aβ deposition was observed in APOE-ε4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-ε4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7-24.6) that is similar to APOE-ε4 homozygous (OR = 9.9, 95% CI = 7.2.9-13.6), and double the risk for APOE-ε4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-ε4 allele, p.E318G is associated with more Aβ plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of Aβ deposition.
Alzheimer's Disease (AD) is a complex and multifactorial disease. While large genome-wide association studies have had some success in identifying novel genetic risk factors for AD, case-control ...studies are less likely to uncover genetic factors that influence progression of disease. An alternative approach to identifying genetic risk for AD is the use of quantitative traits or endophenotypes. The use of endophenotypes has proven to be an effective strategy, implicating genetic risk factors in several diseases, including anemia, osteoporosis and heart disease. In this study we identify a genetic factor associated with the rate of decline in AD patients and present a methodology for identification of other such factors. We have used an established biomarker for AD, cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (ptau(181)) levels as an endophenotype for AD, identifying a SNP, rs1868402, in the gene encoding the regulatory sub-unit of protein phosphatase B, associated with CSF ptau(181) levels in two independent CSF series (P(combined) = 1.17 x 10(-05)). We show no association of rs1868402 with risk for AD or age at onset, but detected a very significant association with rate of progression of disease that is consistent in two independent series (P(combined) = 1.17 x 10(-05)). Our analyses suggest that genetic variants associated with CSF ptau(181) levels may have a greater impact on rate of progression, while genetic variants such as APOE4, that are associated with CSF Aβ(42) levels influence risk and onset but not the rate of progression. Our results also suggest that drugs that inhibit or decrease tau phosphorylation may slow cognitive decline in individuals with very mild dementia or delay the appearance of memory problems in elderly individuals with low CSF Aβ(42) levels. Finally, we believe genome-wide association studies of CSF tau/ptau(181) levels should identify novel genetic variants which will likely influence rate of progression of AD.
Background
Despite the high heritability of alcohol dependence (AD), the genes found to be associated with it account for only a small proportion of its total variability. The goal of this study was ...to identify and analyze phenotypes based on homogeneous classes of individuals to increase the power to detect genetic risk factors contributing to the risk of AD.
Methods
The 7 individual DSM‐IV criteria for AD were analyzed using latent class analysis (LCA) to identify classes defined by the pattern of endorsement of the criteria. A genome‐wide association study was performed in 118 extended European American families (n = 2,322 individuals) densely affected with AD to identify genes associated with AD, with each of the 7 DSM‐IV criteria, and with the probability of belonging to 2 of 3 latent classes.
Results
Heritability for DSM‐IV AD was 61% and ranged from 17 to 60% for the other phenotypes. A single nucleotide polymorphism (SNP) in the olfactory receptor OR51L1 was significantly associated (7.3 × 10−8) with the DSM‐IV criterion of persistent desire to, or inability to, cut down on drinking. LCA revealed a 3‐class model: the “low‐risk” class (50%) rarely endorsed any criteria and none met criteria for AD; the “moderate‐risk” class (33%) endorsed primarily 4 DSM‐IV criteria and 48% met criteria for AD; and the “high‐risk” class (17%) manifested high endorsement probabilities for most criteria and nearly all (99%) met criteria for AD. One SNP in a sodium leak channel NALCN demonstrated genome‐wide significance with the high‐risk class (p = 4.1 × 10−8). Analyses in an independent sample did not replicate these associations.
Conclusions
We explored the genetic contribution to several phenotypes derived from the DSM‐IV AD criteria. The strongest evidence of association was with SNPs in NALCN and OR51L1.
Abstract Background The age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide ...polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA). Methods Genomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs. Results This family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association ( P = 5 × 10−9 ) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 ( ARL15 ) gene on chromosome 5 ( P = 1.11 × 10−8 ) and the UTP20 small subunit ( UTP20 ) gene on chromosome 12 ( P = 4.32 × 10−8 ) that were associated with age at onset of AD. Conclusions This extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD.
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