Faculty Bibliography
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279
Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 x 10(-12)) and X-linked CLDN2 (P < 1 x 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07).
PMCID:3510344
PMID: 23143602
ISSN: 1061-4036
CID: 205272
Comprehensive search for Alzheimer disease susceptibility loci in the APOE region
OBJECTIVE: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN: Conditional logistic regression models and survival analysis. SETTING: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. PARTICIPANTS: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. MAIN OUTCOME MEASURES: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. RESULTS: In models adjusting for APOE epsilon4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of epsilon3/epsilon3 subjects. CONCLUSIONS: APOE alleles epsilon2, epsilon3, and epsilon4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
PMCID:3579659
PMID: 22869155
ISSN: 0003-9942
CID: 627172
Novel late-onset Alzheimer disease loci variants associate with brain gene expression
OBJECTIVE: Recent genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) identified 9 novel risk loci. Discovery of functional variants within genes at these loci is required to confirm their role in Alzheimer disease (AD). Single nucleotide polymorphisms that influence gene expression (eSNPs) constitute an important class of functional variants. We therefore investigated the influence of the novel LOAD risk loci on human brain gene expression. METHODS: We measured gene expression levels in the cerebellum and temporal cortex of autopsied AD subjects and those with other brain pathologies ( approximately 400 total subjects). To determine whether any of the novel LOAD risk variants are eSNPs, we tested their cis-association with expression of 6 nearby LOAD candidate genes detectable in human brain (ABCA7, BIN1, CLU, MS4A4A, MS4A6A, PICALM) and an additional 13 genes +/-100 kb of these SNPs. To identify additional eSNPs that influence brain gene expression levels of the novel candidate LOAD genes, we identified SNPs +/-100 kb of their location and tested for cis-associations. RESULTS: CLU rs11136000 (p = 7.81 x 10(-4)) and MS4A4A rs2304933/rs2304935 (p = 1.48 x 10(-4)-1.86 x 10(-4)) significantly influence temporal cortex expression levels of these genes. The LOAD-protective CLU and risky MS4A4A locus alleles associate with higher brain levels of these genes. There are other cis-variants that significantly influence brain expression of CLU and ABCA7 (p = 4.01 x 10(-5)-9.09 x 10(-9)), some of which also associate with AD risk (p = 2.64 x 10(-2)-6.25 x 10(-5)). CONCLUSIONS: CLU and MS4A4A eSNPs may at least partly explain the LOAD risk association at these loci. CLU and ABCA7 may harbor additional strong eSNPs. These results have implications in the search for functional variants at the novel LOAD risk loci.
PMCID:3398432
PMID: 22722634
ISSN: 0028-3878
CID: 1435652
Abnormal Intracellular Accumulation and Extracellular Abeta Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders
BACKGROUND: It has been shown that amyloid ss (Abeta), a product of proteolytic cleavage of the amyloid beta precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type-specific amount. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Abeta load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Abeta load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Abeta was mainly N-terminally truncated. Increased intraneuronal accumulation of Abeta(17-40/42) in children and adults suggests a life-long enhancement of APP processing with alpha-secretase in autistic subjects. Abeta accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced alpha-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Abeta(1-40/42) detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Abeta and an extracellular deposition of full-length Abeta in nonfibrillar plaques. CONCLUSIONS/SIGNIFICANCE: The higher prevalence of excessive Abeta accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Abeta accumulation and diffuse plaque formation.
PMCID:3342283
PMID: 22567102
ISSN: 1932-6203
CID: 166779
Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants
Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within +/- 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 x 10(-5)-1.67 x 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 x 10(-5)-1.70 x 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics.
PMCID:3369937
PMID: 22685416
ISSN: 1553-7390
CID: 627182
Remission of pre-mild cognitive impairment (MCI), subjective cognitive impairment (SCI): A two-year prospective study of demographic and behavioral markers [Meeting Abstract]
ORIGINAL:0007565
ISSN: 1552-5260
CID: 174416
THE CONCEPT OF RETROGENESIS IN ALZHEIMER'S DISEASE: ETHICAL AND FORENSIC IMPLICATIONS
The concept of retrogenesis has been documented by several studies as the process by which degenerative mechanisms in Alzheimer's disease (AD) reverse the order of acquisition in normal human development. The objective of the present study is to offer expert opinion on the possible ethical and forensic implications of retro genesis. In this regard, we constructed a six-item instrument called 'Questionnaire regarding possible ethical and forensic implications of retrogenesis', which we applied to three professional groups that are directly involved in clinical and forensic evaluation of AD persons, namely, psychiatrists, psychologists and forensic pathologists. The majority of experts questioned in this survey considered it ethical to start from the concept of retrogenesis when approaching AD. Moreover, most of the study participants agreed that it would be ethical to use psychometric tests and programs of cognitive stimulation for the child in the patient with AD. It can also be noted that more than half of the professionals involved in our study considered it ethical to apply child abuse evaluation tests to the AD patients. Furthermore, 61.2% of the opinion survey respondents agreed that it would be necessary to use the concept of retrogenesis for assessing mental capacity in these patients. In addition, most professionals surveyed herein pointed out that it would be necessary to enact legislative proposals on the protection of the patient with AD which would be adapted from the model of the current child protection legislation. This study appears to represent the first expert opinion survey that concerns the ethical and forensic implications of the concept of retrogenesis in AD
ISI:000296480200002
ISSN: 1583-5170
CID: 141093
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 x 10(-9), joint analysis P (P(J)) = 1.7 x 10(-9); stages 1, 2 and 3, P(M) = 8.2 x 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 x 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 x 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 x 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 x 10(-10), P(J) = 5.2 x 10(-11)), CLU (rs1532278; P(M) = 8.3 x 10(-8), P(J) = 1.9 x 10(-8)), BIN1 (rs7561528; P(M) = 4.0 x 10(-14), P(J) = 5.2 x 10(-14)) and PICALM (rs561655; P(M) = 7.0 x 10(-11), P(J) = 1.0 x 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility
PMCID:3090745
PMID: 21460841
ISSN: 1546-1718
CID: 134258
Journal of neuropathology & experimental neurology. 2011:70(1):36-50.DOI: 10.1097/NEN.0b013e318202bfa1
Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome
Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage-proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus, and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68 x of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R tau-positive NFTs in DS/AD subjects compared with that in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS
PMCID:3083064
PMID: 21157379
ISSN: 0022-3069
CID: 134289
A RETROGENIC MODEL FOR DETECTING ABUSE OF INSTITUTIONALIZED PEOPLE WITH ALZHEIMER'S DISEASE
Several studies draw attention to the fact that elder abuse is a complex and multi-dimensional social problem. It has been noticed that institutionalization and disturbing behaviors that result from dementia represent risk factors for mistreatment. In this regard, we have tested if an adapted version of Child Abuse and Trauma Scale can efficiently assess different types of abuse on people with Alzheimer's disease (AD) living in institutional settings. Our choice of an instrument that would ordinarily be used to measure abuse in childhood and adolescence is based on the concept of retrogenesis. This term refers to the process of AD degenerative reversal recapitulation of human ontogenic acquisition patterns. In the present study, we have found that the chosen scale is a reliable screening tool for different forms of abuse in institutionalized AD subjects, providing both a useful, ethically and humanely relevant assessment instrument, and additional evidence for the retrogenesis process. With respect to the frequency of occurrence, neglect and emotional abuse were the most common forms of abuse reported by the study participants, followed by punishment and physical abuse, while sexual abuse was the least reported. Women questioned in this study were found to be more predisposed than men to sexual abuse, while the men were found to be more predisposed to physical abuse. Moreover, the subjects with mild AD reported lower levels of punishment, neglect and emotional abuse when compared to the other AD institutional residents included in this study. In conclusion, our findings will hopefully contribute to the more widespread identification of abuse in persons with dementia, as well as to the development of prevention and intervention strategies
ISI:000290178500002
ISSN: 1583-5170
CID: 133323
