Shahzad Ahmad

Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study

Exploring the role of Alzheimers disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways.

Genetic Determinants of Cortical Structure (Thickness, Surface Area and Volumes) among Disease Free Adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,822 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 161 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.

Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.An increase in the volume of the brain lateral ventricles is a sign of normal aging, but can also be associated with neurological and psychiatric disorders. Here, Vojinovic et al. identify seven genetic loci in a GWA study for ventricular volume in 23,500 individuals and find correlation with thalamus volume.

CIRCULATING METABOLITES ARE ASSOCIATED WITH WHITE MATTER HYPERINTENSITIES

pathways among biological groups by summarizing all pairwise GSEA results. Hierarchical clustering was applied to identify significant interactions between emerged pathways. Results: PCA revealed that rats undergoing perimenopause exhibit substantially higher variances in overall hippocampal gene expression relative to other groups, supporting the perimenopausal brain being in an unstable transition state. While PCA and DEG analyses of hippocampal RNA suggest significant difference among age-matched pre-/peri-/menopause brains, the difference in the hypothalamus was minor, suggesting hippocampus but not hypothalamus as a major brain site affected by endocrine aging. GSEA further revealed alterations in bioenergetic-, inflammatory-, and cell proliferation pathways during the transition featured by declining bioenergetic genes and low-grade activation of immune pathways. Moreover, nuclear(nDNA) or mitochondrial DNA (mtDNA)-encoded bioenergetic genes are differentially regulated by chronologicaland endocrine aging: mtDNA genes correlated closely with chronological aging while nDNA-encoded counterparts were largely endocrine dependent. Lastly, the strong correlation between bioenergetic pathway with genes involved in AD and other neurodegenerative disorders linked bioenergetic deficits to neurodegeneration and elevated AD vulnerability. Conclusions: Our findings suggest that hippocampal gene expression during perimenopause is a transition state characterized by perturbations to primarily bioenergeticand inflammatory pathways, which could contribute to increased AD risk in women. This study provides novel mechanistic insights into the impact of perimenopausal transition on brain function, which could have implications for identifying phenotypes of AD risk for earliest detection in aging females.

CEREBROSPINAL FLUID AND PLASMA LEVELS OF LYSOPHOSPHATIDIC ACIDS (LPAS) ASSOCIATE WITH CEREBROSPINAL FLUID Aβ-42 AND P-TAU

of global and medial temporal lobe atrophy (GCA scale 0-3, MTAscale: 0-4) and white matter hyperintensities (WMH; Fazekas scale; 0-3) with 3 linear regression models; an unadjusted model (model 1), a model including adjustment for sex and age (model 2), and a model including additional adjustment for cardiovascular disease and lipid lowering medication (model 3). The results listed in Table 1 and 2 pass a Bonferroni corrected threshold for significance (p1⁄40.05/1091⁄44.6x10). Results: Thirty-one metabolites were associated with GCA score (Table 1). Lower concentrations of VLDL and triglycerides and higher concentrations of HDL were associated with more atrophy (higher GCA scores). Lower levels of 6 metabolites, including linoleic acid, omega-6 fatty acids and VLDL cholesterol were associated with more WMH (Table 2). Higher levels of citrate and lower levels of histidine were associated with more GCA andMTA (B6SE 0.1160.02, 0.1260.03 for citrate, -0.0960.02, -0.1060.03 for histidine (Figure 1)). The association between lower triglycerides and VLDL levels and higher GCA scores did not alter after correction for clinical variables in Model 2 and 3. Conclusions:Multiple metabolites associate with the extent of neurodegenerative MRI measures. Cholesterol metabolism is important for many processes such as cell membrane structure and synaptic integrity. Previous studies report lower levels of total cholesterol in AD and elevated citrate levels and decreased VLDL particle size predictive for all-causemortality. Perhaps the metabolic changes shown here are systemic markers of frailty in AD.

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome

Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut‐brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimers disease (AD).

Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers

Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co‐metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimers disease (AD) including neuroinflammation and amyloid‐β deposition.

Variants in TTC25 affect autistic trait in patients with autism spectrum disorder and general population

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder with a complex genetic architecture. To identify genetic variants underlying ASD, we performed single-variant and gene-based genome-wide association studies using a dense genotyping array containing over 2.3 million single-nucleotide variants in a discovery sample of 160 families with at least one child affected with non-syndromic ASD using a binary (ASD yes/no) phenotype and a quantitative autistic trait. Replication of the top findings was performed in Psychiatric Genomics Consortium and Erasmus Rucphen Family (ERF) cohort study. Significant association of quantitative autistic trait was observed with the TTC25 gene at 17q21.2 (effect size=10.2, P-value=3.4 × 10−7) in the gene-based analysis. The gene also showed nominally significant association in the cohort-based ERF study (effect=1.75, P-value=0.05). Meta-analysis of discovery and replication improved the association signal (P-valuemeta=1.5 × 10−8). No genome-wide significant signal was observed in the single-variant analysis of either the binary ASD phenotype or the quantitative autistic trait. Our study has identified a novel gene TTC25 to be associated with quantitative autistic trait in patients with ASD. The replication of association in a cohort-based study and the effect estimate suggest that variants in TTC25 may also be relevant for broader ASD phenotype in the general population. TTC25 is overexpressed in frontal cortex and testis and is known to be involved in cilium movement and thus an interesting candidate gene for autistic trait.

GENOMEWIDE LINKAGE ANALYSIS IDENTIFIES NOVEL CANDIDATE GENES FOR ALZHEIMER’S DISEASE

ages 65-79 years. At original enrollment into the trials, women had been randomly assigned to 0.625 mg/d conjugated equine estrogens (CEE) for those with prior hysterectomy (mean 7.1 years), CEE with 2.5 mg/day medroxyprogesterone acetate for thosewith an intact uterus (mean 5.4 years), or matching placebos. Cognitive assessments included telephone evaluations of global cognition, verbal memory, working memory, verbal memory, and executive function. Results: Hormone therapy, when prescribed to women aged 50-54 years, had no significant long-term post-treatment effects on cognitive function or change in cognitive status over time. When prescribed to older women, it was associated with long term mean (SE) relative decrements (standard deviation units) in global cognitive function of 0.081 (0.029) SD, working memory of 0.070 (0.025) SD, and executive function of 0.054 (0.023) SD, all p<0.05. These decrements were relatively stable over time. Findings did not vary depending on the hormone therapy regimen or pre-study use. Although mean intervention effects were small, the largest were comparable in magnitude to those seen during the trial’s active intervention phase. Conclusions: CEE-based hormone therapy delivered near the time of menopause provides neither cognitive benefit nor detriment. If administered in older women, it results in small decrements in several cognitive domains that remain for many years.