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See detailBreast and prostate cancer risk: the interplay of polygenic risk, rare pathogenic germline variants, and family history
Hassanin, Emadeldin; May, Patrick UL; Aldisi, Rana et al

in Genetics in Medicine (2021)

Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods ... [more ▼]

Purpose Investigate to which extent polygenic risk scores (PRS), pathogenic or likely rare pathogenic germline variants (PV), and family history jointly influence breast and prostate cancer risk. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. Heterozygotes or non-heterozygotes of PV in moderate to high cancer risk genes, 2. PRS strata, 3. with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio (OR) across groups and the cumulative incidence through life. Results Cumulative incidence by age 70 among non-heterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast and prostate cancer, respectively. Among PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history is always associated with an increased cancer OR. Conclusion PRS provides a meaningful risk gradient leading alone to a cancer risk comparable to PV in moderate risk genes while acting as risk modifier for high-risk genes. Including family history beside PV and PRS further improves cancer risk stratification. [less ▲]

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See detailDistinct gene-set burden patterns underlie common generalized and focal epilepsies
Koko, Mahmoud; Krause, Roland UL; Sander, Thomas et al

in EBioMedicine (2021), 72

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of ... [more ▼]

Background Analyses of few gene-sets in epilepsy showed a potential to unravel key disease associations. We set out to investigate the burden of ultra-rare variants (URVs) in a comprehensive range of biologically informed gene-sets presumed to be implicated in epileptogenesis. Methods The burden of 12 URV types in 92 gene-sets was compared between cases and controls using whole exome sequencing data from individuals of European descent with developmental and epileptic encephalopathies (DEE, n = 1,003), genetic generalized epilepsy (GGE, n = 3,064), or non-acquired focal epilepsy (NAFE, n = 3,522), collected by the Epi25 Collaborative, compared to 3,962 ancestry-matched controls. Findings Missense URVs in highly constrained regions were enriched in neuron-specific and developmental genes, whereas genes not expressed in brain were not affected. GGE featured a higher burden in gene-sets derived from inhibitory vs. excitatory neurons or associated receptors, whereas the opposite was found for NAFE, and DEE featured a burden in both. Top-ranked susceptibility genes from recent genome-wide association studies (GWAS) and gene-sets derived from generalized vs. focal epilepsies revealed specific enrichment patterns of URVs in GGE vs. NAFE. Interpretation Missense URVs affecting highly constrained sites differentially impact genes expressed in inhibitory vs. excitatory pathways in generalized vs. focal epilepsies. The excess of URVs in top-ranked GWAS risk-genes suggests a convergence of rare deleterious and common risk-variants in the pathogenesis of generalized and focal epilepsies. [less ▲]

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See detailAssessing the role of polygenic background on the penetrance of monogenic forms in Parkinson\textquoterights disease. 2021.06.06.21253270
Hassanin, Emadeldin; May, Patrick UL; Aldisi, Rana et al

E-print/Working paper (2021)

Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease ... [more ▼]

Background: Several rare and common variants are associated with Parkinson's disease. However, there is still an incomplete penetrance in the carriers of rare variants associated with Parkinson's disease. To address this issue, we investigated whether a PRS calculated from significant GWAS SNPs affects the penetrance of Parkinson's disease among carriers of rare monogenic variants in known Parkinson's disease genes and those with a family history. Methods: We calculated the PRS based on common variants and selected the carriers of rare monogenic variants by using the exome data from UK Biobank. Individuals were divided into three risk categories based on PRS: low (<10%), intermediate (10%-90%), and high (>90%) risk groups. We then compared how PRS affects Parkinson\textquoterights disease risk among carriers of rare monogenic variants and those with family-history. Results: We observed a two-fold higher odds ratio for a carrier of a monogenic variant that had a high PRS (OR 4.07,95\% CI, 1.72-8.08) compared to carriers with a low PRS (OR 1.91, 95\% CI, 0.31-6.05). In the same line, carriers with a first-degree family history and with \>90\% PRS have even a higher risk of developing PD (OR 23.53, 95\%CI 5.39-71.54) compared to those with \<90\% PRS (OR 9.54, 95\% CI 3.32-21.65). Conclusions: Our results show that PRS, carrier status, and family history contribute independently and additively to the Parkinson's disease risk. [less ▲]

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See detailBreast and prostate cancer risk: the interplay of polygenic risk, high-impact monogenic variants, and family history 2021.06.04.21258277
Hassanin, Emadeldin; May, Patrick UL; Aldisi, Rana et al

E-print/Working paper (2021)

Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer ... [more ▼]

Purpose: Investigate to which extent polygenic risk scores (PRS), high-impact monogenic variants, and family history affect breast and prostate cancer risk by assessing cancer prevalence and cancer cumulative lifetime incidence. Methods 200,643 individuals from the UK Biobank were stratified as follows: 1. carriers or non-carriers of high impact constitutive, monogenic variants in cancer susceptibility genes, 2. high or non-high PRS (90th percentile threshold), 3. with or without a family history of cancer. Multivariable logistic regression was used to compare the odds ratio (OR) across the different groups while Cox proportional hazards models were used to compute the cumulative incidence through life. Results Breast and prostate cancer cumulative incidence by age 70 is 7 and 5 for non-carriers with non-high PRS and reaches 37 and 32 among carriers of high-impact variants in cancer susceptibility genes with high PRS. The additional presence of family history is associated with a further increase of the risk of developing cancer reaching an OR of 14 and 21 for breast and prostate cancer, respectively. Conclusion: High PRS confers a cancer risk comparable to high-impact monogenic variants. Family history, monogenic variants, and PRS contribute additively to breast and prostate cancer risk. [less ▲]

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See detailA rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Molecular Psychiatry (2020), 25(3), 629-639

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might ... [more ▼]

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, the UK and the USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 α-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD. [less ▲]

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See detailIntestinal-Cell Kinase and Juvenile Myoclonic Epilepsy.
Lerche, Holger; Berkovic, Sam F.; Lowenstein, Daniel H. et al

in New England Journal of Medicine (2019), 380(16), 24

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including ... [more ▼]

With regard to the article by Bailey et al. (March 15, 2018, issue) on the potential role of variants in the gene encoding intestinal cell kinase (ICK) in genetic generalized epilepsies, including juvenile myoclonic epilepsy: We attempted replication by rechecking for enrichment of ICK variants in two previously published analyses of mainly familial cases of genetic generalized epilepsy, which included a total of 1149 cases of genetic generalized epilepsy and 5911 ethnically matched controls. We analyzed the burden of single-gene rare variants with the use of whole exome sequencing data, applying population stratification and both sample and variant quality control. We found no evidence of an enrichment of ICK variants in genetic generalized epilepsies or juvenile myoclonic epilepsy. Specifically, we did not detect a nonsynonymous variant in 357 persons with juvenile myoclonic epilepsy at a minor allele frequency at or below 0.1%. Although we cannot exclude the possibility that ICK variants may be population-specific risk factors for juvenile myoclonic epilepsy, the lack of validation in our cohorts does not support a true disease association but rather suggests that the authors’ results may be due to chance, possibly owing to methodologic issues (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). [less ▲]

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See detailRare gene deletions in genetic generalized and Rolandic epilepsies
Jabbari, Kamel; Bobbili, Dheeraj Reddy UL; Lal, Dennis et al

in PLoS ONE (2018)

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as ... [more ▼]

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE. [less ▲]

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See detailRare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
May, Patrick UL; Girard, Simon; Harrer, Merle et al

in Lancet Neurology (2018), 17(8), 699-708

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We ... [more ▼]

Background Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy. Methods For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes. Findings Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41–4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05–2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02–2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors. Interpretation Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy. [less ▲]

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See detailUNRAVELING THE COMPLEX GENETICS OF NEUROLOGICAL DISORDERS
Bobbili, Dheeraj Reddy UL

Doctoral thesis (2018)

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See detailRare ABCA7 variants in 2 German families with Alzheimer disease
May, Patrick UL; Pichler, Sabrina; Hartl, Daniela et al

in Neurology Genetics (2018), 4(2),

Objective The aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing. Methods Several families with an autosomal dominant ... [more ▼]

Objective The aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing. Methods Several families with an autosomal dominant inheritance pattern of AD were analyzed by whole-genome sequencing. Variants were prioritized for rare, likely pathogenic variants in genes already known to be associated with AD and confirmed by Sanger sequencing using standard protocols. Results We identified 2 rare ABCA7 variants (rs143718918 and rs538591288) with varying penetrance in 2 independent German AD families, respectively. The single nucleotide variant (SNV) rs143718918 causes a missense mutation, and the deletion rs538591288 causes a frameshift mutation of ABCA7. Both variants have previously been reported in larger cohorts but with incomplete segregation information. ABCA7 is one of more than 20 AD risk loci that have so far been identified by genome-wide association studies, and both common and rare variants of ABCA7 have previously been described in different populations with higher frequencies in AD cases than in controls and varying penetrance. Furthermore, ABCA7 is known to be involved in several AD-relevant pathways. Conclusions We conclude that both SNVs might contribute to the development of AD in the examined family members. Together with previous findings, our data confirm ABCA7 as one of the most relevant AD risk genes. [less ▲]

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See detailReply: No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson’s disease
Fitzgerald, Julia C.; Zimprich, Alexander; Bobbili, Dheeraj Reddy UL et al

in Brain : A Journal of Neurology (2018)

Sir, In their letter in this issue, Gaare and colleagues (2018) state that TRAP1 may not be a Parkinson’s disease gene because of lack of genetic association. In response, we welcome their data analyses ... [more ▼]

Sir, In their letter in this issue, Gaare and colleagues (2018) state that TRAP1 may not be a Parkinson’s disease gene because of lack of genetic association. In response, we welcome their data analyses and we welcome any further genetic analyses of TRAP1 variants in additional Parkinson’s disease genetic datasets, including the reanalysis of open access datasets such as the Parkinson’s Progressive Markers Initiative (PPMI). Our point of view is that TRAP1 is an interesting effector protein that our study unequivocally showed is relevant to Parkinson’s disease signaling in the context of mitochondrial regulation. Furthermore, the overall contribution of TRAP1 genetic variants to Parkinson’s disease was not the focus of our recent paper in Brain (Fitzgerald et al., 2017). [less ▲]

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See detailExome-wide analysis of mutational burden in patients with typical and atypical Rolandic Epilepsy
Bobbili, Dheeraj Reddy UL; Lal, Dennis; May, Patrick UL et al

in European Journal of Human Genetics (2018)

Rolandic Epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and Atypical RE (ARE). Here we report on whole ... [more ▼]

Rolandic Epilepsy (RE) is the most common focal epilepsy in childhood. To date no hypothesis-free exome-wide mutational screen has been conducted for RE and Atypical RE (ARE). Here we report on whole-exome sequencing of 194 unrelated patients with RE/ARE and 567 ethnically matched population controls. We identified an exome-wide significantly enriched burden for deleterious and loss-of-function variants only for the established RE/ARE gene GRIN2A. The statistical significance of the enrichment disappeared after removing ARE patients. For several disease-related gene-sets, an odds ratio > 1 was detected for loss-of-function variants. [less ▲]

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See detailMetformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Fitzgerald, Julia C.; Zimprich, Alexander; Carvajal-Berrio, Daniel A. et al

in Brain : A Journal of Neurology (2017), 140(9), 2444-2459

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 ... [more ▼]

The mitochondrial proteins TRAP1 and HtrA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signaling is unclear. HtrA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HtrA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HtrA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HtrA2 and PINK1. HtrA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HtrA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HtrA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies. [less ▲]

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See detailRare variant analysis of the PPMI dataset to uncover the complex genetic architecture of Parkinson’s disease
Bobbili, Dheeraj Reddy UL; May, Patrick UL; Krüger, Rejko UL

in Movement Disorders (2017, June 02), 322(Supplement S2), 405

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s ... [more ▼]

Objective: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). Background: Parkinson’s disease (PD) is a complex disease. Besides variants in high-risk genes such as LRRK2 and PARK2, multiple genes associated to sporadic PD were discovered via genome-wide association studies. Yet, there is a large number of genetic factors that need to be deciphered. Methods: To unravel the genetic factors that play a role in PD we used the whole exome sequencing data available as a part of Parkinson Progression Markers Initiative (PPMI). The dataset comprised of 435 PD cases and 162 ethnically matched controls, respectively. We performed burden tests at single variant, gene and geneset levels on common and rare exonic and splice-variants. We also looked for severity of rare highly deleterious variants (CADD phred score>30) using the CADD score as well as singleton (variants seen in only one individual across cases and controls) rare variants. Additionally, we performed the functional enrichment analysis with the genes harboring rare highly deleterious variants (case uniq genes) that are only present in cases. Results: We observed an increased mutational burden of singleton variants in PD cases compared to the controls in nonsynonymous+LOF variants (empirical P-value 0.005) but not in the synonymous variants (empirical P-value 0.09). We observed a higher significant burden (P-value 0.028) as well as higher significant severity (empirical P-value 0.027) of rare, highly deleterious nonsynonymous variants, but not in the synonymous variants of the candidate genes (P-value 0.686, empirical P-value 0.556 for burden and severity respectively). The network analysis of genes having deleterious variants only present in cases (Case uniq) showed a significant increase in connectivity compared to random networks (P-value 0.0002). Pathway analysis of those genes showed a significant enrichment of pathways and biological process implicated in the nervous system functioning and the etiology of PD. Conclusions: Our study supports the complex disease notion of PD by highlighting the convoluted architecture of PD where case uniq genes including LRRK2 are implicated in several biological processes and pathways related to PD. The main finding of this study is to discover the complex genetics of PD at an exome wide level. [less ▲]

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See detailIDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION
Hartl, Daniela; May, Patrick UL; Gu, Wei UL et al

in Alzheimer's and Dementia: the Journal of the Alzheimer's Association (2017), 13(7, Supplement), 648

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10 ... [more ▼]

Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10. With the advent of whole exome and whole genome sequencing approaches new genes and mutations are likely to be identified. Methods We analyzed the genetic cause of AD in a large multiplex family with an autosomal-dominant pattern of inheritance with LOAD. The family lacked pathogenic mutations of known AD genes. We performed whole-genome sequencing (WGS) in six family members (two affected and four unaffected) and prioritized rare, potential damaging, variants that segregated with disease. Variants were further characterized by subsequent molecular analyzes in human brain and cell culture models. Results We identified a single rare nonsynonymous variant co-segregating with AD. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to a loss-of-function of the gene. We further found a strong negative correlation between the identified gene and APP gene expression in human brain and in cells over-expressing the gene. The negative regulation of APP expression was only observed for the wt gene, but not for mutated forms, thus causing beside the loss of enzyme function a decoupling of both APPexpression and subsequent beta-amyloid formation. The identity of the gene will be presented on the conference. Conclusions This novel pathway strongly supports a causative association of the identified gene with the pathogenesis of AD. [less ▲]

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