2023
Heyne, H O | Karjalainen, J | Karczewski, K J | Lemmelä, S M | Zhou, W | | Havulinna, A S | Kurki, M | Rehm, H L | Palotie, A | Daly, M J
Mono- and biallelic variant effects on disease at biobank scale Journal Article
In: Nature, vol. 613, no. 7944, pp. 519–525, 2023, ISSN: 1476-4687.
Abstract | Links | BibTeX | Tags:
@article{pmid36653560,
title = {Mono- and biallelic variant effects on disease at biobank scale},
author = {H O Heyne and J Karjalainen and K J Karczewski and S M Lemmelä and W Zhou and and A S Havulinna and M Kurki and H L Rehm and A Palotie and M J Daly},
doi = {10.1038/s41586-022-05420-7},
issn = {1476-4687},
year = {2023},
date = {2023-01-01},
journal = {Nature},
volume = {613},
number = {7944},
pages = {519--525},
abstract = {Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Alvarez, Karla Lucia F | Aguilar-Pineda, Jorge Alberto | Ortiz-Manrique, Michelle M | Paredes-Calderon, Marluve F | Cardenas-Quispe, Bryan C | Vera-Lopez, Karin Jannet | Goyzueta-Mamani, Luis D | Chavez-Fumagalli, Miguel Angel | Davila-Del-Carpio, Gonzalo | Peralta-Mestas, Antero | Musolino, Patricia L | Cardenas, Christian Lacks Lino
Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family Journal Article
In: Front Mol Neurosci, vol. 16, pp. 1104585, 2023, ISSN: 1662-5099.
Abstract | Links | BibTeX | Tags:
@article{pmid36873109,
title = {Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family},
author = {Karla Lucia F Alvarez and Jorge Alberto Aguilar-Pineda and Michelle M Ortiz-Manrique and Marluve F Paredes-Calderon and Bryan C Cardenas-Quispe and Karin Jannet Vera-Lopez and Luis D Goyzueta-Mamani and Miguel Angel Chavez-Fumagalli and Gonzalo Davila-Del-Carpio and Antero Peralta-Mestas and Patricia L Musolino and Christian Lacks Lino Cardenas},
doi = {10.3389/fnmol.2023.1104585},
issn = {1662-5099},
year = {2023},
date = {2023-01-01},
journal = {Front Mol Neurosci},
volume = {16},
pages = {1104585},
abstract = {Evidence suggests that there may be racial differences in risk factors associated with the development of Alzheimer's disease and related dementia (ADRD). We used whole-genome sequencing analysis and identified a novel combination of three pathogenic variants in the heterozygous state (: rs7739897 and : rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of affected individuals but absent in healthy members of the family. and studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may affect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our findings have thus identified a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chaisinanunkul, Napasri | Khurshid, Shaan | Buck, Brian H | Rabinstein, Alejandro A | Anderson, Christopher D | Hill, Michael D | Fugate, Jennifer E | Saver, Jeffrey L
How often is occult atrial fibrillation in cryptogenic stroke causal vs. incidental? A meta-analysis Miscellaneous
2023, ISSN: 1664-2295.
Abstract | Links | BibTeX | Tags:
@misc{pmid36998779,
title = {How often is occult atrial fibrillation in cryptogenic stroke causal vs. incidental? A meta-analysis},
author = {Napasri Chaisinanunkul and Shaan Khurshid and Brian H Buck and Alejandro A Rabinstein and Christopher D Anderson and Michael D Hill and Jennifer E Fugate and Jeffrey L Saver},
doi = {10.3389/fneur.2023.1103664},
issn = {1664-2295},
year = {2023},
date = {2023-01-01},
journal = {Front Neurol},
volume = {14},
pages = {1103664},
abstract = {INTRODUCTION: Long-term cardiac monitoring studies have unveiled low-burden, occult atrial fibrillation (AF) in some patients with otherwise cryptogenic stroke (CS), but occult AF is also found in some individuals without a stroke history and in patients with stroke of a known cause (KS). Clinical management would be aided by estimates of how often occult AF in a patient with CS is causal vs. incidental.nnMETHODS: Through a systematic search, we identified all case-control and cohort studies applying identical long-term monitoring techniques to both patients with CS and KS. We performed a random-effects meta-analysis across these studies to determine the best estimate of the differential frequency of occult AF in CS and KS among all patients and across age subgroups. We then applied Bayes' theorem to determine the probability that occult AF is causal or incidental.nnRESULTS: The systematic search identified three case-control and cohort studies enrolling 560 patients (315 CS, 245 KS). Methods of long-term monitoring were implantable loop recorder in 31.0%, extended external monitoring in 67.9%, and both in 1.2%. Crude cumulative rates of AF detection were CS 47/315 (14.9%) vs. KS 23/246 (9.3%). In the formal meta-analysis, the summary odds ratio for occult AF in CS vs. KS in all patients was 1.80 (95% CI, 1.05-3.07), = 0.03. With the application of Bayes' theorem, the corresponding probabilities indicated that, when present, occult AF in patients with CS is causal in 38.2% (95% CI, 0-63.6%) of patients. Analyses stratified by age suggested that detected occult AF in patients with CS was causal in 62.3% (95 CI, 0-87.1%) of patients under the age of 65 years and 28.5% (95 CI, 0-63.7%) of patients aged 65 years and older but estimates had limited precision.nnCONCLUSION: Current evidence is preliminary, but it indicates that in cryptogenic stroke when occult AF is found, it is causal in about 38.2% of patients. These findings suggest that anticoagulation therapy may be beneficial to prevent recurrent stroke in a substantial proportion of patients with CS found to have occult AF.},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
Rämö, Joel T | Kiiskinen, Tuomo | Seist, Richard | Krebs, Kristi | Kanai, Masahiro | Karjalainen, Juha | Kurki, Mitja | Hämäläinen, Eija | Häppölä, Paavo | Havulinna, Aki S | Hautakangas, Heidi | | Mägi, Reedik | Palta, Priit | Esko, Tõnu | Metspalu, Andres | Pirinen, Matti | Karczewski, Konrad J | Ripatti, Samuli | Milani, Lili | Stankovic, Konstantina M | Mäkitie, Antti | Daly, Mark J | Palotie, Aarno
Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure Journal Article
In: Nat Commun, vol. 14, no. 1, pp. 157, 2023, ISSN: 2041-1723.
Abstract | Links | BibTeX | Tags:
@article{pmid36653343,
title = {Genome-wide screen of otosclerosis in population biobanks: 27 loci and shared associations with skeletal structure},
author = {Joel T Rämö and Tuomo Kiiskinen and Richard Seist and Kristi Krebs and Masahiro Kanai and Juha Karjalainen and Mitja Kurki and Eija Hämäläinen and Paavo Häppölä and Aki S Havulinna and Heidi Hautakangas and and Reedik Mägi and Priit Palta and Tõnu Esko and Andres Metspalu and Matti Pirinen and Konrad J Karczewski and Samuli Ripatti and Lili Milani and Konstantina M Stankovic and Antti Mäkitie and Mark J Daly and Aarno Palotie},
doi = {10.1038/s41467-022-32936-3},
issn = {2041-1723},
year = {2023},
date = {2023-01-01},
journal = {Nat Commun},
volume = {14},
number = {1},
pages = {157},
abstract = {Otosclerosis is one of the most common causes of conductive hearing loss, affecting 0.3% of the population. It typically presents in adulthood and half of the patients have a positive family history. The pathophysiology of otosclerosis is poorly understood. A previous genome-wide association study (GWAS) identified a single association locus in an intronic region of RELN. Here, we report a meta-analysis of GWAS studies of otosclerosis in three population-based biobanks comprising 3504 cases and 861,198 controls. We identify 23 novel risk loci (p < 5 × 10) and report an association in RELN and three previously reported candidate gene or linkage regions (TGFB1, MEPE, and OTSC7). We demonstrate developmental stage-dependent immunostaining patterns of MEPE and RUNX2 in mouse otic capsules. In most association loci, the nearest protein-coding genes are implicated in bone remodelling, mineralization or severe skeletal disorders. We highlight multiple genes involved in transforming growth factor beta signalling for follow-up studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Natarajan, Pradeep | Manne, Munikumar | Koduru, Swetha Kumari | Bokkasam, Teja Sree
3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent Journal Article
In: Cancer Treat Res Commun, vol. 36, pp. 100744, 2023, ISSN: 2468-2942.
Abstract | Links | BibTeX | Tags:
@article{pmid37481995,
title = {3-deazaadenosine: A promising novel p38γ antagonist with potential as a breast cancer therapeutic agent},
author = {Pradeep Natarajan and Munikumar Manne and Swetha Kumari Koduru and Teja Sree Bokkasam},
doi = {10.1016/j.ctarc.2023.100744},
issn = {2468-2942},
year = {2023},
date = {2023-01-01},
journal = {Cancer Treat Res Commun},
volume = {36},
pages = {100744},
abstract = {Human p38γ protein kinase, or MAPK12, is a crucial signaling protein that is important in channelizing membrane signals to the nucleus in the MAPK cascade pathway, associated with breast and colorectal cancer, besides other forms of malignancies and atherosclerotic lesions too. P38γ has a significant contribution to the progression of breast carcinoma due to its multifaceted functions. Targeting p38γ for defining potent antagonists against p38γ can turn out to be an attractive and novel means of breast cancer therapeutics. Novel and potent lead molecules were designed utilizing computational drug design methodologies. Using high-throughput virtual screening, 1909 geometrically similar analogs of known inhibitors were generated, primarily using BIRB796, SB202190, ANP, CHEBI: 620708, and CHEBI: 524699. Chemical correctness was ensured using LigPrep for the standalone library, and Prep Wizard for p38γ using Maestro v.11.5. Using the Glide v5.5 flexible docking procedure on a standalone library of p38γ binding sites, we defined 18 potential leads and assessed their ADMET properties. Lead "1", among the proposed four p38γ antagonists with high-scoring and favorable interactions, was considered for 100 ns molecular dynamics simulations. Among the four proposed leads, Lead '1' displayed consistent and stable bonding interactions with p38γ throughout the 100 ns molecular dynamics (MD) simulations. Additionally, it formed water bridges, contributing to its strong association with the protein. Notably, Lead '1' (3-deazaadenosine) exhibited favorable root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) within the acceptable range of pharmacological properties. Thus, 3-deazaadenosine and its mimetic might be promising new directions for developing a novel class of antagonists for breast cancer treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}