Kim-Dung Huynh

PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα (PRKCA) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.

Cholesterol 25-Hydroxylase on Chromosome 10q Is a Susceptibility Gene for Sporadic Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5′ region of CH25H revealed three common haplotypes, CH25Hχ2, CH25Hχ3 and CH25Hχ4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hχ4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain Aβ deposits in carriers of CH25Hχ4 and CH25Hχ3 haplotypes, whereas no Aβ deposits were present in CH25Hχ2 carriers. Together, these results are compatible with a role of CH25Hχ4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain Aβ deposition.

Association study of cholesterol-related genes in Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples.

CPEB3 is associated with human episodic memory

Cytoplasmic polyadenylation element-binding (CPEB) proteins are crucial for synaptic plasticity and memory in model organisms. A highly conserved, mammalian-specific short intronic sequence within CPEB3 has been identified as a ribozyme with self-cleavage properties. In humans, the ribozyme sequence is polymorphic and harbors a single nucleotide polymorphism that influences cleavage activity of the ribozyme. Here we show that this variation is related to performance in an episodic memory task and that the effect of the variation depends on the emotional valence of the presented material. Our data suggest a role for human CPEB3 in human episodic memory.

Fine-mapping at the HTR2A locus reveals multiple episodic memory-related variants

A functional polymorphism (His452Tyr) in the gene encoding the serotonin 2A receptor (HTR2A) has been previously associated with human episodic memory performance and with differences in brain volume in memory-related brain regions. Here we present data obtained through imputation and fine-mapping showing that multiple loci within HTR2A are significantly associated with human memory performance independently of the His452Tyr polymorphism. Our data support the existence of multiple memory-related loci within HTR2A.

Age-dependent effects of the 5-hydroxytryptamine-2a-receptor polymorphism (His452Tyr) on human memory.

A polymorphism (His452Tyr) of the 5-hydroxytryptamine (5-HT)2a receptor is associated with episodic memory in healthy young humans. Because 5-HT2a-receptor density decreases with increasing age, we tested whether the 5-HT2a receptor genotype effect on memory is influenced by age. We investigated the association of the His452Tyr genotype with memory performance in 622 healthy study participants aged from 18 to 90 years. In young to middle-aged participants, age significantly influenced genotype effects on episodic memory: the His452Tyr genotype exerted a significant influence on memory only in young participants. In the group of elderly cognitively healthy participants, the His452Tyr genotype did not affect memory performance. We conclude that age strongly modulates the effect of the 5-HT2a receptor polymorphism at residue 452 on episodic memory.

No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits

A 30 cM broad genomic region on the long arm of chromosome 10 at 80 cM shows significant and consistent linkage with AD and with plasma concentration of the β‐amyloid peptide 1–42 (Aβ42). The PLAU gene, which is involved in the production and degradation of Aβ42, maps to that region and is therefore a strong positional candidate for association with sporadic AD. We analyzed the non‐synonymous single nucleotide polymorphism (SNP) rs2227564 in two independent case‐control series from Switzerland and Greece and investigated the influence of this SNP on cognition in elderly individuals. Because PLAU modulates the cleavage of the amyloid precursor protein (APP) and the degradation of Aβ, we also determined the levels of Aβ in the brain, plasma and in the cerebrospinal fluid (CSF). We found no evidence for association of this SNP with AD or with AD‐related traits such as β‐amyloid load in the medial temporal lobe or Aβ42 concentration in the CSF and in plasma. Our findings do not support a major role of PLAU polymorphisms as susceptibility factors for AD and suggest that large‐scale association studies which combine genetic information from populations with similar genetic background might prevent the generation of spurious associations. Although PLAU may be pathophysiologially related to AD, the contribution of common genetic variants of this gene to the risk for developing AD is likely to be low.

Human genome–guided identification of memory-modulating drugs

Significance In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. Here, we report that by using genomic information related to aversive memory—a trait central to posttraumatic stress disorder—we identified several potential drug targets and compounds. In a subsequent pharmacological study with one of the identified compounds, we found a drug-induced reduction of aversive memory. These findings indicate that genomic information can be used as a starting point for the identification of memory-modulating compounds. In the last decade there has been an exponential increase in knowledge about the genetic basis of complex human traits, including neuropsychiatric disorders. It is not clear, however, to what extent this knowledge can be used as a starting point for drug identification, one of the central hopes of the human genome project. The aim of the present study was to identify memory-modulating compounds through the use of human genetic information. We performed a multinational collaborative study, which included assessment of aversive memory—a trait central to posttraumatic stress disorder—and a gene-set analysis in healthy individuals. We identified 20 potential drug target genes in two genomewide-corrected gene sets: the neuroactive ligand–receptor interaction and the long-term depression gene set. In a subsequent double-blind, placebo-controlled study in healthy volunteers, we aimed at providing a proof of concept for the genome-guided identification of memory modulating compounds. Pharmacological intervention at the neuroactive ligand–receptor interaction gene set led to significant reduction of aversive memory. The findings demonstrate that genome information, along with appropriate data mining methodology, can be used as a starting point for the identification of memory-modulating compounds.