Unraveling the genetic architecture of blood unfolded p-53 among non-demented elderlies: novel candidate genes for early Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a heritable neurodegenerative disease whose long asymptomatic phase makes the early diagnosis of it pivotal. Blood U-p53 has recently emerged as a superior predictive biomarker for AD in the early stages. We hypothesized that genetic variants associated with blood U-p53 could reveal novel loci and pathways involved in the early stages of AD. RESULTS: We performed a blood U-p53 Genome-wide association study (GWAS) on 484 healthy and mild cognitively impaired subjects from the ADNI cohort using 612,843 Single nucleotide polymorphisms (SNPs). We performed a pathway analysis and prioritized candidate genes using an AD single-cell gene program. We fine-mapped the intergenic SNPs by leveraging a cell-type-specific enhancer-to-gene linking strategy using a brain single-cell multimodal dataset. We validated the candidate genes in an independent brain single-cell RNA-seq and the ADNI blood transcriptome datasets. The rs279686 between AASS and FEZF1 genes was the most significant SNP (p-value = 4.82 × 10-7). Suggestive pathways were related to the immune and nervous systems. Twenty-three candidate genes were prioritized at 27 suggestive loci. Fine-mapping of 5 intergenic loci yielded nine cell-specific candidate genes. Finally, 15 genes were validated in the independent single-cell RNA-seq dataset, and five were validated in the ADNI blood transcriptome dataset. CONCLUSIONS: We underlined the importance of performing a GWAS on an early-stage biomarker of AD and leveraging functional omics datasets for pinpointing causal genes in AD. Our study prioritized nine genes (SORCS1, KIF5C, TMEFF2, TMEM63C, HLA-E, ATAT1, TUBB, ARID1B, and RUNX1) strongly implicated in the early stages of AD.

Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.

Polycystic liver disease (PLD) is a rare condition observed in three genetic diseases, including autosomal dominant polycystic liver disease (ADPLD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). PLD usually does not impair liver function, and advanced PLD becomes symptomatic when the enlarged liver compresses adjacent organs or increases intra-abdominal pressure. Currently, the diagnosis of PLD is mainly based on imaging, and genetic testing is not required except for complex cases. Besides, genetic testing may help predict patients' prognosis, classify patients for genetic intervention, and conduct early treatment. Although the underlying genetic causes and mechanisms are not fully understood, previous studies refer to primary ciliopathy or impaired ciliogenesis as the main culprit. Primarily, PLD occurs due to defective ciliogenesis and ineffective endoplasmic reticulum quality control. Specifically, loss of function mutations of genes that are directly involved in ciliogenesis, such as Pkd1, Pkd2, Pkhd1, and Dzip1l, can lead to both hepatic and renal cystogenesis in ADPKD and ARPKD. In addition, loss of function mutations of genes that are involved in endoplasmic reticulum quality control and protein folding, trafficking, and maturation, such as PRKCSH, Sec63, ALG8, ALG9, GANAB, and SEC61B, can impair the production and function of polycystin1 (PC1) and polycystin 2 (PC2) or facilitate their degradation and indirectly promote isolated hepatic cystogenesis or concurrent hepatic and renal cystogenesis. Recently, it was shown that mutations of LRP5, which impairs canonical Wnt signaling, can lead to hepatic cystogenesis. PLD is currently treated by somatostatin analogs, percutaneous intervention, surgical fenestration, resection, and liver transplantation. In addition, based on the underlying molecular mechanisms and signaling pathways, several investigational treatments have been used in preclinical studies, some of which have shown promising results. This review discusses the clinical manifestation, complications, prevalence, genetic basis, and treatment of PLD and explains the investigational methods of treatment and future research direction, which can be beneficial for researchers and clinicians interested in PLD.

Association of the APOE gene variants with depression in type 2 diabetes.

Background: The risk of depression among patients with diabetes is higher than the general population. The exact mechanisms linking these two diseases are mostly unknown. Energy metabolism disorders seem to be a shared pathway. One of the key genes playing important roles in energy metabolism-related pathways is the APOE gene. We aimed to investigate the association of the APOE gene variants with depression among Iranian patients with type 2 diabetes (T2DM). Methods: Three APOE gene alleles and genotypes frequencies (E2, E3, E4) were determined in 244 patients with T2DM (114 with depression and 130 without depression) using the high-resolution melting (HRM) method on the genomic DNA extracted from the patient's peripheral blood. Results: Apoe4 allele frequency was significantly higher in T2DM patients without depression compared with those with depression (11.9 vs. 2.2%, p-value < 0.0001 and p-value = 0.001, respectively). Conversely, the wild allele apoe3 frequency was significantly higher in T2DM patients with depression (86% vs., 69%, p-value < 0.0001). Apoe4 carrier status was associated with decreased risk of depression in patients with T2DM [OR: 0.19 (0.07-0.53)]. Conclusion: Our results showed that the apoe4 allele and apoe4 carrier status significantly reduced the risk of depression among patients with T2DM. Further studies are needed to unravel the complex role of the APOE gene in depression among patients with diabetes.

Genome- and Exome-Wide Association Studies Revealed Candidate Genes Associated with DaTscan Imaging Features.

Introduction: Despite remarkable progress in identifying Parkinson's disease (PD) genetic risk loci, the genetic basis of PD remains largely unknown. With the help of the endophenotype approach and using data from dopamine transporter single-photon emission computerized tomography (DaTscan), we identified potentially involved genes in PD. Method: We conducted an imaging genetic study by performing exome-wide association study (EWAS) and genome-wide association study (GWAS) on the specific binding ratio (SBR) of six DaTscan anatomical areas between 489 and 559 subjects of Parkinson's progression markers initiative (PPMI) cohort and 83,623 and 36,845 single-nucleotide polymorphisms (SNPs)/insertion-deletion mutations (INDELs). We also investigated the association of cerebrospinal fluid (CSF) protein concentration of our significant genes with PD progression using PPMI CSF proteome data. Results: Among 83,623 SNPs/INDELs in EWAS, one SNP (rs201465075) on 1 q32.1 locus was significantly (P value = 4.03 × 10-7) associated with left caudate DaTscan SBR, and 33 SNPs were suggestive. Among 36,845 SNPs in GWAS, one SNP (rs12450112) on 17 p.12 locus was significantly (P value = 1.34 × 10-6) associated with right anterior putamen DaTscan SBR, and 39 SNPs were suggestive among which 8 SNPs were intergenic. We found that rs201465075 and rs12450112 are most likely related to IGFN1 and MAP2K4 genes. The protein level of MAP2K4 in the CSF was significantly associated with PD progression in the PPMI cohort; however, proteomic data were not available for the IGFN1 gene. Conclusion: We have shown that particular variants of IGFN1 and MAP2K4 genes may be associated with PD. Since DaTscan imaging could be positive in other Parkinsonian syndromes, caution should be taken when interpreting our results. Future experimental studies are also needed to verify these findings.

The prevalence and predictors of geriatric giants in community-dwelling older adults: a cross-sectional study from the Middle East.

The term "geriatric giants" refers to the chronic disabilities of senescence leading to adverse health outcomes. This study aimed to investigate the prevalence and predictors of geriatric giants in Southern Iran. The participants were selected from Bushehr city using a multistage cluster random sampling method. Demographic data were collected through interviews. Frailty, incontinence, immobility, depression, cognitive impairment, and malnutrition were measured by questionnaires and instruments. Finally, data from 2392 participants were analyzed. The prevalence of fecal incontinence was less than 1% among all participants and similar in men and women. In contrast, compared with men, women had higher prevalence of urinary incontinence (36.44% vs. 17.65%), depression (39.05% vs. 12.89%), anorexia and malnutrition (2.35% vs. 0.82%), immobility (8.00% vs. 2.5%), frailty (16.84 vs. 7.34), and pre-frailty (54.19 vs. 38.63%). The prevalence of dependence and cognitive impairment was also higher in women and considerably increased with the age of participants. In total, 12.07% of subjects were frail, and 46.76% were pre-frail. The prevalence of frailty exponentially increased in older age, ranging from 4.18% among those aged 60-64 years to 57.35% in those aged ≥ 80 years. Considering 95% confidence interval (CI), multivariate logistic regression revealed that low physical activity [odds ratio (OR) 31.73 (18.44-54.60)], cancer (OR 3.28 (1.27-8.44)), depression [OR 2.42 (1.97-2.98)], age [OR 1.11 (1.08-1.14)], waist circumference [OR 1.03 (1.01-1.06)], BMI [OR 1.07 (1.01-1.14)], MNA score [OR 0.85 (0.79-0.92)], polypharmacy [OR 2.26 (1.30-3.95)] and male gender [OR 0.63 (0.42-0.93)] were independently associated with frailty. White blood cell count (WBC), smoking, marital status, and number of comorbidities were not independently associated with frailty. Low physical activity was the strongest predictor of frailty, which may need more attention in geriatric care. Frailty, its predictors, and other components of geriatric giants were considerably more common among women and older ages.

TMPRSS2 polymorphism (rs12329760) and the severity of the COVID-19 in Iranian population.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been responsible for the recent pandemic since early 2020. Due to the wide range of clinical symptoms of this disease, from asymptomatic to severe and critical forms, it seems that genetic differences among patients, along with other factors (such as gender, age, and underlying diseases), can explain part of the variation in disease symptoms. The TMPRSS2 enzyme plays a vital role in the early stages of the interaction of the SARS-CoV-2 with the host cells by facilitating viral entry. There is a polymorphism in the TMPRSS2 gene, called rs12329760(C to T) as a missense variant, which causes the replacement of valine to methionine in the TMPRSS2 protein at position 160. The present study investigated the association between the TMPRSS2 genotype and the severity of the Coronavirus disease 2019 (COVID-19) in Iranian patients. The TMPRSS2 genotype of 251 COVID-19 patients (151 patients with asymptomatic to mild and 100 patients with severe to critical symptoms) was detected on genomic DNA extracted from patients' peripheral blood via the ARMS-PCR method. Our results showed a significant association between the minor T allele and the severity of the COVID-19 (P-value = 0.043) under the dominant and additive inheritance model. In conclusion, the results of this study showed that the T allele of the rs12329760 in the TMPRSS2 gene is a risk allele for severe form of COVID-19 in Iranian patients in contrast to most previous studies on this variant in European ancestry populations which suggested this variant as a protective allele. Our results reiterate to the ethnic-specific risk alleles and hidden unknown complexity behind the host genetic susceptibility. However, further studies are needed to address the complex mechanisms behind the interaction of the TMPRSS2 protein and the SARS-CoV-2 and the role of rs12329760 polymorphism in determining the disease severity.