Rodney T. Perry

ApoE-4 and Age at Onset of Alzheimer's Disease The NIMH Genetics Initiative

Objective: To explore the impact of apoE-4 on Alzheimers disease (AD) and its age at onset. Design: A genetic linkage study using affected relative pairs, predominantly siblings. Setting: Three academic medical centers ascertained subjects from memory disorder clinics, nursing homes, and the local community. Subjects: 310 families including 679 subjects with AD by NINCDS/ADRDA and/or Khachaturian criteria and 231 unaffected subjects. Outcome measure: ApoE genotype. Analytic methods: Association, affected pedigree member, sibling pair, and lod score analyses. Results: ApoE-4 was strongly associated with AD in this sample (allele frequency = 0.46 vs. 0.14 in controls, p < 0.000001). Results of lod score, affected pedigree member analysis, and sib-pair analysis also supported apoE-4 as a risk factor for AD. When the sample was stratified on family mean age at onset, the risk conferred by apoE-4 was most marked in the 61 to 65 age group. Individuals with two copies of apoE-4 had a significantly lower age at onset than those with one or no copies (66.4 vs. 72.0, p < 0.001), but individuals with one copy did not differ from those with none. Within families, the individual with the earliest age at onset had, on average, significantly more apoE-4 alleles (p < 0.0001) than the individual with the latest onset. Discussion: This work supports previous reports of an association between apoE-4 and the development of AD and demonstrates that apoE-4 exerts its maximal effect before age 70. These findings have important implications for the potential use of apoE genotyping for diagnosis and prediction of disease. They also underscore the need to identify additional genetic factors involved in AD with onset beyond age 70 years. NEUROLOGY 1997;48: 139-147

The role of TNF and its receptors in Alzheimer’s disease

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that is upregulated in Alzheimer disease (AD) patients and involved with AD genes. Several TNF promoter polymorphisms that increase expression are associated with inflammatory and infectious diseases. We previously reported results that detected a AD associated region near the TNF gene. Using family-based association tests we also reported an association between AD and a TNF haplotype in sibling-pair families, and a significant increase in the mean age of onset for a group of African-American AD patients carrying this same haplotype. Previous reports have shown that that the chromosome 1p and chromosome 12p regions are linked to late-onset AD. These two regions harbor TNF receptors (TNFR) 2 and 1, respectively, and binding to them mediates biological effects of TNF. We found a significant asssociation of a TNFR2 exon 6 polymorphism with late-onset AD in families with no individuals possessing the APOE E4E4 genotype under a dominant model. We found no significant association of three polymorphisms in the TNFR1 gene to AD. These results provide further evidence for the involvement of TNF in the pathogenesis of AD.

Repeat Expansion in C9ORF72 in Alzheimer's Disease

A hexanucleotide repeat expansion in the gene C9ORF72 has been implicated in the development of amyotrophic lateral sclerosis and frontotemporal dementia. The variant has also been found in a small percentage of patients with probable late-onset Alzheimers disease.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: The NIMH Alzheimer disease genetics initiative

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Neuregulin-1 polymorphism in late onset Alzheimer's disease families with psychoses

Probands with late onset Alzheimers disease (LOAD) exhibit positive symptoms of psychosis, 30–60% of the time. Positive symptoms of psychosis have been shown to appear prior to the onset of dementia to be accompanied by greater cognitive deficits, and to predict a more rapid decline. A study of the distribution of AD with psychosis (ADP) in families from the NIMH Alzheimers Disease Genetic Initiative sample indicates that the trait is heritable, and linkage studies of multiplex ADP families have found suggestive peaks on 2p, 6q, 8p, and 21q. A genome scan of idiopathic psychosis, schizophrenia, in the Icelandic population identified a risk haplotype within the 5′ region of neuregulin‐1 (NRG1) on 8p12. Associations with NRG1 SNPs have also been found in other schizophrenia populations from Scotland, Ireland, and China. Here, we report results demonstrating a significant linkage peak for ADP on 8p12 in the NIMH AD dataset, encompassing the NRG1 region. We also demonstrate that there is a significant association with a NRG1 SNP (single nucleotide polymorphism), rs392499, with ADP, χ2 = 7.0, P = 0.008. This same SNP is part of a 3‐SNP haplotype preferentially transmitted to individuals with this phenotype. Our results suggest that NRG1 plays a role in increasing the genetic risk to positive symptoms of psychosis in a proportion of LOAD families.

Association of DNA Methylation Differences With Schizophrenia in an Epigenome-Wide Association Study

IMPORTANCE DNA methylation may play an important role in schizophrenia (SZ), either directly as a mechanism of pathogenesis or as a biomarker of risk. OBJECTIVE To scan genome-wide DNA methylation data to identify differentially methylated CpGs between SZ cases and controls. DESIGN, SETTING, AND PARTICIPANTS Epigenome-wide association study begun in 2008 using DNA methylation levels of 456 513 CpG loci measured on the Infinium HumanMethylation450 array (Illumina) in a consortium of case-control studies for initial discovery and in an independent replication set. Primary analyses used general linear regression, adjusting for age, sex, race/ethnicity, smoking, batch, and cell type heterogeneity. The discovery set contained 689 SZ cases and 645 controls (n = 1334), from 3 multisite consortia: the Consortium on the Genetics of Endophenotypes in Schizophrenia, the Project among African-Americans To Explore Risks for Schizophrenia, and the Multiplex Multigenerational Family Study of Schizophrenia. The replication set contained 247 SZ cases and 250 controls (n = 497) from the Genomic Psychiatry Cohort. MAIN OUTCOMES AND MEASURES Identification of differentially methylated positions across the genome in SZ cases compared with controls. RESULTS Of the 689 case participants in the discovery set, 477 (69%) were men and 258 (37%) were non-African American; of the 645 controls, 273 (42%) were men and 419 (65%) were non-African American. In our replication set, cases/controls were 76% male and 100% non-African American. We identified SZ-associated methylation differences at 923 CpGs in the discovery set (false discovery rate, <0.2). Of these, 625 showed changes in the same direction including 172 with P < .05 in the replication set. Some replicated differentially methylated positions are located in a top-ranked SZ region from genome-wide association study analyses. CONCLUSIONS AND RELEVANCE This analysis identified 172 replicated new associations with SZ after careful correction for cell type heterogeneity and other potential confounders. The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for SZ.

Genetic Variation in NCAM1 Contributes to Left Ventricular Wall Thickness in Hypertensive Families

Rationale: Left ventricular (LV) mass and related phenotypes are heritable, important predictors of cardiovascular disease, particularly in hypertensive individuals. Objective: Identify genetic predictors of echocardiographic phenotypes in hypertensive families. Methods and Results: A multistage genome-wide association study (GWAS) was conducted in hypertensive-ascertained black families (HyperGEN, stage I; GENOA, stage II); findings were replicated in HyperGEN white families (stage III). Echocardiograms were collected using a common protocol, and participants were genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The following were analyzed using mixed models adjusted for ancestry: in stages I and II, 1258 and 989 blacks, respectively; and in stage III, 1316 whites. Phenotypes included LV mass, LV internal dimension (LVID), wall thicknesses (posterior [PWT] and intraventricular septum [IVST]), and relative wall thickness (RWT). In stage I, 5 single nucleotide polymorphisms (SNPs) had P⩽10−6. In stage II, 1 SNP (rs1436109; NCAM1 intron 1) replicated with the same phenotype (PWT, P=0.025) in addition to RWT (P=0.032). In stage III, rs1436109 was associated with RWT (P=5.47×10−4) and LVID (P=1.86×10−4). Fisher combined probability value for all stages was RWT=3.80×10−9, PWT=3.12×10−7, IVST=8.69×10−7, LV mass=2.52×10−3, and LVID=4.80×10−4. Conclusions: This GWAS conducted in hypertensive families identified a variant in NCAM1 associated with LV wall thickness and RWT. NCAM is upregulated during the remodeling period of hypertrophy to heart failure in Dahl salt–sensitive rats. Our initial screening in hypertensive blacks may have provided the context for this novel locus.

Genetic Association of Neurotrophic Tyrosine Kinase Receptor Type 2 (NTRK2) With Alzheimer's Disease†‡

Brain‐derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long‐term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin‐3 (NT‐3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimers disease (AD). This study is the most comprehensive investigation of genetic variants of NTRK2, and the first to show significant association between NTRK2 with AD. Fourteen single nucleotide polymorphisms (SNPs), located in 8 of 18 linkage disequilibrium (LD) blocks, were genotyped in 203 families with at least two AD affected siblings with mean age of onset (MAO) of 70.9 ± 7.4 years and one unaffected sibling from the NIMH‐ADGJ dataset. Family based association testing found no single SNP association, however, significant associations were found for two and three locus haplotypes (P = 0.012, P = 0.009, respectively) containing SNPs rsl624327, rsl443445, and rs378645. These SNPs are located in areas of the gene containing sequences that could be involved in alternative splicing and/or regulation of NTRK2. Our results suggest that NTRK2 may be a genetic susceptibility gene contributing to AD pathology.

Effects of chronic stress and interleukin-10 gene polymorphisms on antibody response to tetanus vaccine in family caregivers of patients with Alzheimer's disease.

Objective: To assess the effects of psychological stress on the antibody response to tetanus vaccine adjusting for cytokine gene polymorphisms and other nongenetic factors in caregivers of patients with Alzheimer’s disease (AD). Methods: A family-based follow-up study was conducted in 119 spouses and offspring of community-dwelling patients with AD. Psychological stress was measured by the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D) scale at baseline and 1 month after the vaccination. Nutritional status, health behaviors, comorbidity, and stress-buffering factors were assessed by self-administered questionnaires, 10 single nucleotide polymorphisms (SNP) from six selected cytokines genotyped, and anti-tetanus toxoid immunoglobulin G (IgG) concentrations tested using enzyme-linked immunosorbent assays. The effects of stress and other potential confounders were assessed by mixed models that account for familial correlations. Results: The baseline PSS score, the baseline CES-D score, the interleukin-10–1082 A>G SNP GG genotype, and the baseline anti-tetanus IgG were inversely associated with antibody fold increase. Conclusion: Both psychological stress and cytokine gene polymorphisms affected antibody fold increase. The study provided additional support for the detrimental effects of psychological stress on the antibody response to tetanus vaccine. AD = Alzheimer’s disease; CES-D = Center for Epidemiologic Studies Depression; PSS = Perceived Stress Scale; ELISA = enzyme-linked immunosorbent assays; SNP = single nucleotide polymorphisms.

Further evidence of a maternal parent-of-origin effect on chromosome 10 in late-onset Alzheimer’s disease

The chromosome 10q region has recently received a great deal of attention in late‐onset Alzheimers disease (LOAD), given the growing evidence of linkage to LOAD, or to A‐beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD genetics initiative pedigrees, approaching genome‐wide significance (non‐parametric LOD score = 3.27), when only families with maternal disease origin were analyzed [Bassett et al. (2002); Am J Med Genet 114:679–686]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent‐of‐origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine‐mapping work on this region and five new markers genotyped in all pedigrees results in a non‐parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical P value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent‐of‐origin information has been useful in further narrowing the region of interest.