Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Sklan, Ella H.; Lowenthal, Alexander; Korner, Mira; Ritov, Ya’acov; Landers, Daniel M.; Rankinen, Tuomo; Bouchard, Claude; Leon, Arthur S.; Rice, Treva; Rao, D. C.; Wilmore, Jack H.; Skinner, James S.; Soreq, Hermona

doi:10.1073/pnas.0307659101

Cited by 125 publications

(95 citation statements)

References 51 publications

(47 reference statements)

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“…Cholinergic status values improved pulse predictions even when controlled for all other risk factors in men but not in women (24), compatible with the antiinflammatory effect of cholinergic signaling (14) as well as with previous reports of protective acetylcholine effects on ischemic myocardium (26), and with the pulse improvement effects of the AChE inhibitor pyridostigmine (27).…”

Section: Significancesupporting

confidence: 86%

See 1 more Smart Citation

Fear and C-reactive protein cosynergize annual pulse increases in healthy adults

Shenhar‐Tsarfaty

Yayon

Waiskopf

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Recent international terror outbreaks notably involve long-term mental health risks to the exposed population, but whether physical health risks are also anticipated has remained unknown. Here, we report fear of terror-induced annual increases in resting heart rate (pulse), a notable risk factor of all-cause mortality. Partial least squares analysis based on 325 measured parameters successfully predicted annual pulse increases, inverse to the expected age-related pulse decline, in approximately 4.1% of a cohort of 17,380 apparently healthy active Israeli adults. Nonbiased hierarchical regression analysis among 27 of those parameters identified pertinent fear of terror combined with the inflammatory biomarker C-reactive protein as prominent coregulators of the observed annual pulse increases. In comparison, basal pulse primarily depended on general physiological parameters and reduced cholinergic control over anxiety and inflammation, together indicating that consistent exposure to terror threats ignites fear-induced exacerbation of preexisting neuro-immune risks of all-cause mortality.pulse | terror | C-reactive protein | acetylcholinesterase | cholinergic status R ecent international terror outbreaks involve mass psychological trauma, leading to long-term mental health risks in the exposed population (1, 2). Fear-induced reactions involve cortical and limbic brain regions that together enhance threatpredictive sensory stimuli (3) by interacting with cholinergic signaling pathways (4) in the hippocampus (5), the central amygdala (6), and the prefrontal cortex, especially in adults (7). Imminent fear may even cause immediate cardiac death [e.g., after an earthquake (8)]. However, whether fear exposure elevates cardiac risks of death to otherwise healthy civilians, and if so, what are the causes of such risks, remains unknown.Pulse is a promising modifiable predictor of cardiovascular and all-cause mortality. Elevated pulse associates with increased systemic inflammation and endothelial dysfunction in older adults (9) and predicts increased risk of death from ischemic heart disease (10). Changes in basal pulse and pulse variability are tightly associated with sudden cardiac death and all-cause mortality, also in asymptomatic men (11). Pulse reflects a complex trait, determined by multiple genetic, environmental, and other endogenous factors that play a substantial role in population variation (12). These include excessive inflammation, shown to associate with pulse increases (13), to be controlled by cholinergic imbalance (decreased vagal tone or increased sympathetic activity) (14), and to increase mortality (15). However, whether specific psychological factors determine the basal pulse and annual pulse changes in active adults is still unknown, perhaps because the intensity of psychological phenomena largely depends on external sources and is highly variable.Although fear of terror (FOT) is universal, Israel has been exposed to the repeated stress of multiple wars and terror attacks for more than 60 y, with a ma...

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Section: Significancesupporting

confidence: 86%

“…Additionally, addition of cholinesterase activity to the model of pulse prediction yields a significant measure in men, but not women ( Fig. 5A; R 2 change = 0.03, F change = 3.6, P = 0.03), compatible with the sex-related nature of cholinergic status and inflammation values (24).…”

Section: Significancesupporting

confidence: 53%

Fear and C-reactive protein cosynergize annual pulse increases in healthy adults

Shenhar‐Tsarfaty

Yayon

Waiskopf

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…A goal of genomewide association studies is to identify genotype patterns that contribute to a specific phenotype, as genes may interact with each other to produce disease and analysis of genotype patterns may reflect such joint gene effects better than looking at one gene at a time. [59][60][61] Information revealed by genotype patterns is more accurate than that from haplotypes, which are generally derived from statistical programs and not measured directly. 62 Using the three autosomal variants with the highest significance by association of genotype frequency with heroin addiction, we employed a strategy in which variants from different genes were analyzed together to identify common genotype patterns of unlinked alleles that are associated with heroin addiction.…”

Section: Discussionmentioning

confidence: 99%

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

Nielsen

Yuferov

et al. 2008

Mol Psychiatry

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A genome-wide association study was conducted using microarray technology to identify genes that may be associated with the vulnerability to develop heroin addiction, using DNA from 104 individual former severe heroin addicts (meeting Federal criteria for methadone maintenance) and 101 individual control subjects, all Caucasian. Using separate analyses for autosomal and X chromosomal variants, we found that the strongest associations of allele frequency with heroin addiction were with the autosomal variants rs965972, located in the Unigene cluster Hs.147755 (experiment-wise q = 0.053), and rs1986513 (q = 0.187). The three variants exhibiting the strongest association with heroin addiction by genotype frequency were rs1714984, located in an intron of the gene for the transcription factor myocardin (P = 0.000022), rs965972 (P = 0.000080) and rs1867898 (P = 0.000284). One genotype pattern (AG-TT-GG) was found to be significantly associated with developing heroin addiction (odds ratio (OR) = 6.25) and explained 27% of the population attributable risk for heroin addiction in this cohort. Another genotype pattern (GG-CT-GG) of these variants was found to be significantly associated with protection from developing heroin addiction (OR = 0.13), and lacking this genotype pattern explained 83% of the population attributable risk for developing heroin addiction. Evidence was found for involvement of five genes in heroin addiction, the genes coding for the l opioid receptor, the metabotropic receptors mGluR6 and mGluR8, nuclear receptor NR4A2 and cryptochrome 1 (photolyase-like). This approach has identified several new genes potentially associated with heroin addiction and has confirmed the role of OPRM1 in this disease.

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“…AChE-R is rare in brains of nonstressed laboratory mice, but might be more common in freeliving mammals that experience many types of stress on a regular basis. The hypothesis that variation in basal expression of the AChE-R isoform affects a variety of behavioral phenotypes is supported by the finding that in healthy human volunteers, blood serum levels of monomeric, circulating AChE-R protein show a significant inverse relationship with anxiety ( Figure 1d; Sklan et al, 2004). Fearful behavior in mice maps to multiple loci on different chromosomes (Gershenfeld and Paul, 1997), and it would be interesting to determine if any of these loci encode or interact with upstream regulators of AChE or its splice factors.…”

Section: As and The Generation Of Plastic Organism-level Phenotypesmentioning

confidence: 92%

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

Marden

2006

Heredity

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Alternative splicing (AS) of pre-messenger RNA is a common phenomenon that creates different transcripts from a single gene, and these alternative transcripts affect phenotypes. The majority of AS research has examined tissue and developmental specificity of expression of particular AS transcripts, how this specificity affects cell function, and how aberrant AS is related to disease. Few studies have examined quantitative between-individual variation in AS within a cell or tissue type, or in relation to phenotypes, but the results are compelling: quantitative variation in AS affects plastic traits such as stress, anxiety, fear, egg production, muscle performance, energetics and plant growth. Genomic analyses of AS are also at a nascent stage, but have revealed a number of significant evolutionary patterns. Growing knowledge of upstream genes and kinases that regulate AS provides the as-yet little explored potential to examine how these genes and pathways respond to environmental and genotype variables. Research in this area can provide glimpses of a labyrinth of genetic architectures that have rarely been considered in evolutionary and organismal biology, or in quantitative genetics. The scarcity of contribution to knowledge about AS from these fields is illustrated by the fact that heritability of quantitative variation in AS has not yet been determined for any gene in any organism. New research tactics that incorporate quantitative analyses of AS will allow organismal and evolutionary biologists to attain a fuller mechanistic understanding of many of the traits they study, and may lead to more rapid discovery of functionally important polymorphisms.

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Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Cited by 125 publications

References 51 publications

Fear and C-reactive protein cosynergize annual pulse increases in healthy adults

Fear and C-reactive protein cosynergize annual pulse increases in healthy adults

Genotype patterns that contribute to increased risk for or protection from developing heroin addiction

Quantitative and evolutionary biology of alternative splicing: how changing the mix of alternative transcripts affects phenotypic plasticity and reaction norms

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