Genome‐wide study of the human lipidome and links to Alzheimer’s disease risk

Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer’s disease (AD). One limitation in understanding BIN1’s contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1–LVGCC interactions were modulated by Tau in rat hippocampal neurons and mouse brain. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1’s neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.

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Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

10.1101/258533 ◽

2018 ◽

Cited By ~ 14

Author(s):

Iris E Jansen ◽

Jeanne E Savage ◽

Kyoko Watanabe ◽

Julien Bryois ◽

Dylan M Williams ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genome Wide Association Study ◽

Disease Risk ◽

Late Onset ◽

Meta Analysis ◽

Genetic Correlations ◽

Cell Types ◽

Mendelian Randomisation ◽

Genome Wide

AbstractLate onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.

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Sex differences in the genetic predictors of Alzheimer’s pathology

Brain ◽

10.1093/brain/awz206 ◽

2019 ◽

Vol 142 (9) ◽

pp. 2581-2589 ◽

Cited By ~ 13

Author(s):

Logan Dumitrescu ◽

Lisa L Barnes ◽

Madhav Thambisetty ◽

Gary Beecham ◽

Brian Kunkle ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Disease Risk ◽

Association Studies ◽

Age At Onset ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Data Repositories ◽

Genome Wide

Abstract 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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Variants in PPP2R2B and IGF2BP3 are associated with higher tau deposition

Brain Communications ◽

10.1093/braincomms/fcaa159 ◽

2020 ◽

Author(s):

Vijay K Ramanan ◽

Xuewei Wang ◽

Scott A Przybelski ◽

Sheelakumari Raghavan ◽

Michael G Heckman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Risk ◽

Regulatory Gene ◽

Functional Characterization ◽

Regulatory Subunit ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Tau Pet

Abstract Tau deposition is a key biological feature of Alzheimer’s disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of in vivo assessment of tau burden through PET provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study (GWAS) of tau-PET on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test SNP associations with AV-1451 (18F-flortaucipir) tau-PET burden in an Alzheimer’s-signature composite region of interest, using an additive genetic model and covarying for age, sex, and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (p=9.91 x 10−9, β = 0.20) in the tau phosphorylation regulatory gene PPP2R2B (protein phosphatase 2 regulatory subunit B) and for rs117402302 (p=4.00 x 10−8, β = 0.19) near IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3). The PPP2R2B association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the IGF2BP3 association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three SNPs within MAPT (microtubule-associated protein tau) displayed nominal associations with tau-PET burden, and the association of the APOE (apolipoprotein E) ɛ4 allele with tau-PET was marginally nonsignificant (p=0.06, β = 0.07). No associations with tau-PET burden were identified for other SNPs associated with Alzheimer’s disease clinical diagnosis in prior large case-control studies. Our findings nominate PPP2R2B and IGF2BP3 as novel potential influences on tau pathology which warrant further functional characterization. Our data is also supportive of previous literature on the associations of MAPT genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer’s susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.

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Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk

Translational Psychiatry ◽

10.1038/s41398-021-01272-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daichi Shigemizu ◽

Risa Mitsumori ◽

Shintaro Akiyama ◽

Akinori Miyashita ◽

Takashi Morizono ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Japanese Population ◽

Disease Risk ◽

Association Studies ◽

Meta Analysis ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome

AbstractAlzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including APOE and SORL1, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus FAM47E reached genome-wide significance in a meta-analysis of association results. This is the first report associating the FAM47E locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in OR2B2. Our data highlight the importance of performing GWAS in non-European populations.

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