rs11136000

This study demonstrates that the CR1 locus (rs6656401) is associated with faster cognitive decline and greater Alzheimer's disease neuropathology in an aging population. The effect on cognition is substantially mediated through increased amyloid plaque burden, with 43% of the global cognition effect and 60% of the episodic memory effect attributable to amyloid pathology. The study analyzed two prospective cohort studies with 1,666 total participants and neuropathological examination in 553 deceased subjects.

This case-control study attempted to replicate the association of TOMM40 polyT polymorphism (rs10524523) with Alzheimer's disease risk and age at onset. In a large series of 1594 LOAD cases and 1190 controls, the study failed to replicate the previously reported association with age at onset but found a significant association between rs10524523 and risk for LOAD among APOE 33 homozygotes in the opposite direction (OR=0.78, 95% CI=0.65-0.95; p=0.004, allele frequencies 0.41 vs 0.48 in cases vs controls). No association was found between rs10524523 and CSF biomarker levels (tau, phosphorylated tau, Aβ42) or TOMM40/APOE gene expression.

This comprehensive genome-wide association study examined genetic variants contributing to late-onset Alzheimer's disease (AD) in 513 African American cases and 496 controls, plus replication in 5 white cohorts. The APOE ε4 allele showed strong association (P=9.69×10⁻²³), and after adjusting for APOE, rs6859 in PVRL2 remained significantly associated (P=0.0087). The study found associations with variants in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, though effect directions sometimes differed from white populations. Novel associations with suggestive evidence were identified in PROX1, CNTNAP2, STK24, and other genes, though not replicated in whites.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

This 3-stage genome-wide association meta-analysis study identified 5 novel and confirmed loci associated with late-onset Alzheimer's disease across over 35,000 individuals. The study discovered two new genome-wide significant loci: rs744373 in BIN1 (OR 1.13, p=1.59×10⁻¹¹) and rs597668 near EXOC3L2 (OR 1.18, p=6.45×10⁻⁹), and confirmed three previously reported loci in APOE (OR 2.53, p=1.04×10⁻²⁹⁵), CLU (OR 0.85, p=1.62×10⁻¹⁶), and PICALM (OR 0.89, p=3.16×10⁻¹²). These findings were validated in an independent Spanish replication sample of 2,349 individuals.

A case-control study of 740 individuals from the Alzheimer's Disease Neuroimaging Initiative investigated whether genome-wide association study (GWAS)-validated and GWAS-promising candidate loci influence magnetic resonance imaging measures and clinical Alzheimer's disease status. APOE showed the strongest association with clinical diagnosis (OR=2.07, p<1×10⁻⁶). Among previously validated non-APOE loci, only CR1 (rs1408077, OR=1.27, p=0.02) replicated. GWAS-promising variants at BIN1 (rs7561528, OR=1.29, p=0.03) and CNTN5 (rs10501927, OR=1.25, p=0.03) also showed significant associations with AD diagnosis, and a cumulative genetic risk score combining APOE, CLU, PICALM, CR1, BIN1, and CNTN5 variants predicted increased severity across multiple neuroimaging measures.

This replication study confirms associations between three novel Alzheimer's disease genes (CLU, CR1, and PICALM) and late-onset Alzheimer's disease (LOAD) in an independent cohort of 1,829 LOAD cases and 2,576 controls. The study found CLU rs11136000 (OR=0.82, p=8.6×10⁻⁵), CR1 rs3818361 (OR=1.15, p=0.014), and PICALM rs3851179 (OR=0.80, p=1.3×10⁻⁵) showed comparable direction and magnitude of effect to initial GWAS reports, providing strong independent validation for these novel LOAD susceptibility genes.

This meta-analysis of 7,070 Alzheimer's disease cases and 8,169 cognitively normal elderly controls from 12 independent cohorts confirms that variants in CR1, CLU, and PICALM are AD risk loci in European ancestry populations (CLU rs11136000 OR=0.91, CR1 rs3818361 OR=1.14, PICALM rs3851179 OR=0.89). The study reveals a synergistic interaction between PICALM and APOE ε4, with PICALM association predominantly observed in APOE ε4-positive subjects.

This comprehensive review synthesizes genomic and pharmacogenomic research in schizophrenia, discussing over 200 candidate genes associated with psychotic disorders, genetic mechanisms including copy number variants and microRNA alterations, and pharmacogenomic factors affecting antipsychotic efficacy and safety. Key genes covered include dopamine receptors (DRD1-5), dysbindin (DTNBP1), DISC1, neurotrophic factors, and metabolic enzymes such as CYP2D6, CYP3A4, and COMT, with emphasis on genotype-phenotype correlations in antipsychotic response and side effects.

A review of genetic discoveries in Alzheimer's disease using cerebrospinal fluid (CSF) levels of amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau181) as endophenotypes. The paper discusses multiple GWAS and sequencing studies that identified novel AD risk variants including rs9877502 (3q28, p=4.89×10⁻⁹), rs514716 in GLIS3 (p=1.07×10⁻⁸), and rs6922617 in TREM cluster (p=3.58×10⁻⁸), as well as functional characterization of known AD variants including APOE, MAPT, and TREM2. The review emphasizes the increased statistical power of using quantitative CSF biomarkers compared to traditional case-control designs.