Association of a neurokinin 3 receptor polymorphism with the anterior basal forebrain

Teipel, Stefan J.; Grothe, Michel J.; Wittfeld, Katharina; Hoffmann, Wolfgang; Hegenscheid, Katrin; Völzke, Henry; Homuth, Georg; Grabe, Hans J.

doi:10.1016/j.neurobiolaging.2014.12.031

Cited by 9 publications

(8 citation statements)

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“…The relationship between alexithymia and gray matter volume was investigated by Grabe et al [ 18 ] as the main correlate in subjects with alexithymia ( n = 1685), resulting in a reduction in brain volume in DACC. Teipel et al [ 63 ] investigated the association of the rs2765 single-nucleotide polymorphism (SNP of the NK3 receptor) coding gene TACR3 with the magnetic resonance imaging volume of the basal anterior lobe and hippocampus ( n = 1967). The results suggested an association.…”

Section: Resultsmentioning

confidence: 99%

“…Here, too, a single sequence was predominantly used, the magnetization prepared rapid acquisition gradient echo sequence (MPRAGE). This provided a set of isometric voxels in T1 weighting [ 17 , 39 , 40 , 46 , 49 , 54 , 62 , 63 , 64 , 66 ]. Depending on the aim of the studies, different methods and software packages (e.g., FreeSurfer, SPM, FSL, or inhouse solutions) were applied to preprocess the data, extract MRI phenotypes, or conduct voxel-based morphometry analyses.…”

Section: Discussionmentioning

confidence: 99%

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SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center

et al. 2021

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The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center

et al. 2021

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“…Stimulation of NK3-R significantly enhances learning and memory performance in aged rats [68]. Furthermore, a SNP located in 3'-UTR of TACR3 is associated with learning performance, hippocampal volume in elderly human patients [68], and the most anterior basal forebrain volume [69]. The association of rs144292455, a nonsense variant in TACR3, provides more evidence for its potential involvement in AD.…”

Section: Discussionmentioning

confidence: 99%

Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease

Loika

Park

et al. 2020

Preprint

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Despite recent discovery in GWAS of genomic variants associated with Alzheimer's disease (AD), its underlying biological mechanisms are still elusive. Discovery of novel AD-associated genetic variants, particularly in coding regions and from APOE ε 4 non-carriers, may provide more insights into the understanding of the pathology of AD. In this study, we carried out exome-wide association analysis of age-of-onset of AD with ~20,000 subjects, and placed more emphasis on APOE ε 4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing three new variants. We identified two novel rare variants, rs56201815, a synonymous variant in ERN1, from the analysis of APOE ε 4 noncarriers, and a missense variant rs144292455 in TACR3. In addition, we detected rs12373123, a common missense variant in SPPL2C in the MAPT region, associated with age-of-onset of AD in APOE ε 4 non-carriers. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including posterior cingulate cortex and nucleus accumbens. Our cell type-specific eQTL analysis of based on ~80,000 single nuclei in prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also provide more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson's disease.In this study, we performed exome-wide association analysis of age-of-onset of AD, in which most genetic variants are rare or low frequency, using an Alzheimer's Disease Sequencing Project (ADSP) sample of 10,216 subjects in the discovery phase. Rare coding variants often show larger effect size and their biological consequences are more explicable, but its association analysis is complicated by insufficient statistical power. Although exome-wide association of AD has recently been explored using AD status (Bis et al., 2018;Cruchaga et al., 2014;Raghavan et al., 2018), our rationale is that more AD-related rare variants can be identified using analysis of age-of-onset of AD with a Cox model given emerging evidence from a previous study showing its advantage in terms of statistical power (He and Kulminski, 2019). We attempted to replicate significant findings in four other studies, with a meta-analysis sample size of a...

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“…Segmentation of cholinergic cell groups in the basal forebrain cannot be based on visual features of the cells in MR images (Teipel et al, 2015; Wolf et al, 2014). Therefore, we have to assume that volumetric data of the BFCS have relatively more noise contamination than brain volume which can be segmented by voxel intensity.…”

Section: Discussionmentioning

confidence: 99%

“…Atrophy of cholinergic cells in the basal forebrain is also seen in healthy elderly subjects without clinical evidence of dementia (Grothe et al, 2012, 2013; Teipel et al, 2015). Post mortem studies reported a decrease of histological markers of ACh-synthesis and cholinergic synapses during normal ageing which is accelerated in AD patients (Sparks et al, 1992; Perry et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly

et al. 2018

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Association of a neurokinin 3 receptor polymorphism with the anterior basal forebrain

Cited by 9 publications

References 43 publications

SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center

SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center

Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease

Basal forebrain cholinergic system volume is associated with general cognitive ability in the elderly

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