scholarly journals Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases

2013 ◽  
Author(s):  
Bora E Baysal
Keyword(s):  
Natural Selection ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Complex Diseases ◽  
World Health ◽  
Common Disease ◽  
Common Diseases ◽  
Age Related

Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset). Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases. Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases. Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.

scholarly journals Natural selection increases mutational robustness in complex diseases: Mendelian evidence from early versus late onset common diseases

2013 ◽  
Author(s):  
Bora E Baysal
Keyword(s):  
Natural Selection ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Phenotypic Expression ◽  
Complex Diseases ◽  
World Health ◽  
Common Disease ◽  
Common Diseases ◽  
Age Related

Background. Natural selection operates on genetically influenced phenotypic variations that confer differential survival or reproductive advantages. Common diseases are frequently associated with increased mortality and disability and complex heritable factors play an important role in their pathogenesis. Hence, common diseases should trigger the process of natural selection with subsequent population genetic response. However, empirical impact of natural selection on genetics of complex diseases is poorly understood. In this paper, I hypothesize that negative selection of diseased individuals leads to systemic genetic differences between common diseases that primarily occur before or during the reproductive years (early onset) and those that occur after the reproductive years (late onset). Methods. To test this hypothesis, a comprehensive literature survey of highly penetrant (80% or more) nonpleiotropic, nonsyndromic susceptibility genes (hereafter defined as Mendelian phenocopies) was completed for early versus late onset common diseases, organized using the World Health Organization (WHO) ICD-10 classification scheme. An average age at sporadic disease onset of 30 years was selected for dividing early versus late onset common diseases. Results. Mendelian phenocopies were identified for 16 primarily late onset common diseases from 9 distinct WHO diagnostic categories. Late onset common diseases with Mendelian phenocopies include papillary renal carcinoma, obesity, Alzheimer disease, Parkinson disease, frontotemporal dementia, amyotrophic lateral sclerosis, primary open angle glaucoma, age-related hearing loss, coronary artery disease, stroke, pancreatitis, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, inclusion body myositis, Paget's disease of bone and focal segmental glomerulosclerosis (steroid resistant). In contrast, no Mendelian phenocopy was found for any primarily early onset common disease (p<5.8x10-4). Thus, highly predictive rare variants are present for a subset of late onset common diseases, but not for early onset common diseases. Discussion. These findings suggest that genetic architecture of early onset common diseases is more robust against the phenotypic expression of highly penetrant predisposing mutations than is the case for late onset common diseases. The primary candidate for increased genetic robustness in early onset common diseases is proposed to be natural selection.

scholarly journals Early-onset vs. Late-onset Parkinson’s disease: A Clinical-pathological Study

2015 ◽  
Vol 43 (1) ◽  
pp. 113-119 ◽  
Author(s):  
Leslie Wayne Ferguson ◽  
Ali H. Rajput ◽  
Alexander Rajput
Keyword(s):  
Parkinson Disease ◽  
Early Onset ◽  
Disease Duration ◽  
Late Onset ◽  
Disease Onset ◽  
Clinic Visit ◽  
Pathological Study ◽  
Younger Age ◽  
Wearing Off ◽  
Selection For

AbstractBackground:Several studies have compared early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD) but most are not based on autopsy confirmed cases.Methods:We compared clinical and pharmacological profiles, time to reach irreversible Hoehn and Yahr (H&Y) Stage 3 and levodopa motor complications in autopsy confirmed EOPD and LOPD cases.Results:At first clinic visit EOPD cases were younger but had longer disease duration and they died at a younger age (all p<0.0001). Anti-Parkinsonian drug use, including levodopa, was significantly delayed in EOPD. Lifetime use of amantadine (p<0.05) and dopamine agonists (p<0.01) were higher in EOPD. While lifetime use of levodopa was similar in the two groups, levodopa was used for a significantly longer period by EOPD (p< 0.0001). EOPD had a higher cumulative incidence of dyskinesias (p<0.01), wearing-off (p<0.01), and on-off (p<0.01). However, the time to dyskinesia onset was similar in the two groups. The threshold to wearing-off was much longer in EOPD (p<0.01). H&Y stage profile at first visit was similar in the two groups. The duration from disease onset to reach irreversible H&Y stage 3 was significantly longer in EOPD.Conclusions:Our observations indicate that progression of PD is slower in EOPD and suggest that the pre-clinical interval in this group is longer. These findings can be used for case selection for drug trials and studies of the pathogenesis of PD.

Genetic Insights into Early-onset Parkinson’s Disease

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 41
Author(s):  
Roy N Alcalay ◽  
Cheryl Waters ◽  
◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Early Onset ◽  
Late Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Leucine Rich Repeat ◽  
Strong Family History ◽  
Early Onset Parkinson’S Disease

Early-onset Parkinson’s disease (EOPD) is defined as disease onset before 40 or 50 years of age. The clinical characteristics of EOPD are very similar to those of late-onset PD, but dystonia is more often a presenting symptom, dementia is rare, and disease progression may be slower. Mutations in several genes have been described in cases with EOPD, often with strong family history, including mutations in α-synuclein (SNCA),DJ-1, PTEN-induced kinase-1 (PINK-1), andATP13A2. However, the most common mutations identified in EOPD are in Parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2), and glucocerebrosidase (GBA). With the exception ofSNCAandATP13A2carriers, mutation carriers are often indistinguishable from non-carriers. Large series of EOPD cases that are not ascertained by family history estimate mutation frequency at 4–16%. Given that the frequency of positive family history is much higher, we believe that many genetic risk factors are yet to be discovered.

scholarly journals Leptin Receptor (rs1137101) and Brain-Derived Neurotrophic Factor (rs925946) Gene Variants Are Associated with Obesity in the Early- but Not in the Late-Onset Population of Hungarian Psoriatic Patients

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1086
Author(s):  
Zita Szentkereszty-Kovács ◽  
Szilvia Fiatal ◽  
Eszter Anna Janka ◽  
Dóra Kovács ◽  
Andrea Szegedi ◽  
...  
Keyword(s):  
Early Onset ◽  
Leptin Receptor ◽  
Late Onset ◽  
Disease Onset ◽  
Patient Characteristics ◽  
Population Based ◽  
Gene Variants ◽  
Increased Risk ◽  
Hungarian Population ◽  
Control Study

Background: Psoriatic patients have considerably higher odds of being obese compared with the general population; however, the exact pathophysiological link between psoriasis and obesity needs to be elucidated. Methods: To investigate the association of psoriasis with established obesity-related gene variants, we conducted a population-based case-control study including 3541 subjects (574 psoriasis cases and 2967 controls from the general Hungarian population). Genotyping of 20 SNPs at ADIPOQ, BDNF, FTO, GNPDA2, LEPR, MC4R, NEGR1, NPY, PPARG, TMEM18, and UCP2 were determined, and differences in genotype and allele distributions were investigated. Multiple logistic regression analyses were implemented. Results: Analysis revealed an association between the G allele of the rs1137101 polymorphism (LEPR gene) and obesity risk (OR: 3.30 (1.45; 7.50), p = 0.004) in the early-onset group of psoriatic patients. Furthermore, the T allele of rs925946 polymorphism (BDNF gene) was also associated with increased risk of obesity in early-onset psoriasis (OR: 2.26 (1.24; 4.14) p = 0.008). Conclusions: Our results suggest that in psoriatic patients, there are prominent differences in the causes of obesity that should be accounted for, including not only environmental factors but also patient characteristics, such as the time of disease onset as well as genetic factors.

Related Heterogeneity in Pathologically Confirmed Sporadic Alzheimer Disease

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011772
Author(s):  
Denis S Smirnov ◽  
Douglas Galasko ◽  
Annie Hiniker ◽  
Steven Edland ◽  
David P. Salmon
Keyword(s):  
Early Onset ◽  
Age Of Onset ◽  
Late Onset ◽  
Functional Decline ◽  
Apoe Genotype ◽  
Executive Dysfunction ◽  
Bimodal Distribution ◽  
Cognitive Testing ◽  
Apoe Ε4 ◽  
Age Related

Objective:To characterize age-related clinical heterogeneity in Alzheimer’s disease (AD) and determine if it is modified by APOE genotype or concomitant non-AD pathology, we analyzed data from 1750 patients with sporadic, pathologically-confirmed severe AD.Methods:In this retrospective cohort study, regression and mixed effects models assessed effects of estimated age of onset, APOE genotype, and their interaction on standardized clinical, cognitive and pathologic outcome measures from the National Alzheimer’s Coordinating Center (NACC) database.Results:A bimodal distribution of age of onset frequency in APOE ε4- cases showed best separation at age 63. Using this age cut-off, cases were grouped as early onset (EO) AD ε4- (n=169), EOAD ε4+ (n=273), late onset (LO) AD ε4- (n=511), and LOAD ε4+ (n=797). EOAD were more likely than LOAD patients to present with non-cognitive behavioral or motor symptoms or non-memory cognitive complaints, and had more executive dysfunction, but less language impairment on objective cognitive testing. Age of onset and ε4- genotype were independently associated with lower baseline MMSE and greater functional impairment, and EOAD had faster cognitive and functional decline than LOAD regardless of APOE genotype. EOAD were more likely than LOAD patients to receive a non-AD clinical diagnosis even though they were more likely to have “pure” AD without concomitant vascular or other non-AD neurodegenerative pathology.Conclusions:Early onset sporadic AD is associated with a greater likelihood of an atypical, non-memory dominant clinical presentation, especially in the absence of the APOE ε4 allele, which may lead to misattribution to non-AD underlying pathology.

Cardiac functions and aortic elasticity in children with inflammatory bowel disease: effect of age at disease onset

2020 ◽  
Vol 30 (3) ◽  
pp. 313-317
Author(s):  
Elif Erolu ◽  
Esra Polat
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Early Onset ◽  
Late Onset ◽  
Disease Onset ◽  
Left Ventricular ◽  
Control Group ◽  
Aortic Elasticity ◽  
Cardiac Functions ◽  
Inflammatory Bowel

AbstractAim:Childhood onset inflammatory bowel disease is more aggressive and has rapidly progressive clinical course than adult inflammatory bowel disease. Early-onset inflammatory bowel disease has more severe clinical progression as a subspecialised group of monogenic inflammatory bowel disease. We studied cardiac functions and aortic elasticity in children with early- and late-onset inflammatory bowel disease in remission period.Methods:Thirty-three paediatric patients were divided into subgroups according to age of disease onset (<10 and >10 years of age). Twenty-five healthy children were admitted as control group. M-Mode echocardiography and pulsed wave Doppler echocardiography were performed. Strain, distensibility, stiffness index of ascending, and abdominal aorta were evaluated.Results:Interventricular septum (mm) and left ventricular end-systolic diameter were higher (6.9 ± 1.2, 26.2 ± 4.6) in early-onset inflammatory bowel disease patients than control patients (6.1 ± 1.27, 22.7 ± 4.12) (p = 0.050, p = 0.050). Mitral E/E′ ratio and myocardial performance index were increased in inflammatory bowel disease and early-onset inflammatory bowel disease groups than control group (p = 0.046, p = 0.04; p = 0.023, p = 0.033). Diastolic functions were found to be impaired in inflammatory bowel disease and early-onset inflammatory bowel disease groups according to control group, while there was no difference between late-onset inflammatory bowel disease and control groups in terms of diastolic functions. Mitral E/A ratio was lower in inflammatory bowel disease patients and early-onset inflammatory bowel disease patients (1.46 ± 0.32, 1.4 ± 0.21) than control patients (1.70 ± 0.27) (p = 0.013, p = 0.004). Aortic elasticity did not differ between groups.Conclusion:Chronic low-grade inflammation has effects on left ventricular diameters and diastolic function in remission period. Aortic elasticity is not affected in our study groups.

Effect of Age at Onset on Disease Characteristics in Vitiligo

2013 ◽  
Vol 17 (4) ◽  
pp. 253-258 ◽  
Author(s):  
Amrinder J. Kanwar ◽  
Rahul Mahajan ◽  
Davinder Parsad
Keyword(s):  
Early Onset ◽  
Late Onset ◽  
Statistical Significance ◽  
Age At Onset ◽  
Positive Family History ◽  
Disease Onset ◽  
Disease Characteristics ◽  
The Difference ◽  
Trauma Stress ◽  
Distinguishing Features

Background: Vitiligo is a multifactorial disease in which genetic, immunologic, and environmental factors play an important part. Late-onset vitiligo is a poorly defined entity. Materials and Methods: Case records of patients who attended the pigmentary clinic at our institute from January 2001 to December 2010 were reviewed. Patients with a diagnosis of vitiligo were analyzed with respect to their demographic characteristics with special reference to their age at onset. Results: Patients with disease onset after 30 years had a significantly higher association with precipitating factors such as trauma, stress, and drugs in comparison with early-onset vitiligo ( p < .004). However, the difference did not reach statistical significance when these factors were analyzed individually. There was a significantly higher association with other nonautoimmune diseases ( p = .05), a higher incidence of positive family history ( p < .0001), and a higher association with leukotrichia ( p < .002) in late-onset disease. Early-onset nonsegmental vitiligo was associated with a higher incidence of photosensitivity and pruritus compared to early-onset segmental vitiligo. Conclusion: Late-onset vitiligo has certain distinguishing features compared to early-onset vitiligo.

scholarly journals DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2589
Author(s):  
Jihoon E. Joo ◽  
Mark Clendenning ◽  
Ee Ming Wong ◽  
Christophe Rosty ◽  
Khalid Mahmood ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Early Onset ◽  
Late Onset ◽  
Normal Mucosa ◽  
Accelerated Ageing ◽  
Normal Colonic Mucosa ◽  
Age Related ◽  
Differentially Methylated Genes ◽  
Early Onset Colorectal Cancer

We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50–70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10−16) and young people without CRC (p = 5.8 × 10−6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.

scholarly journals A Practical Approach to Early-Onset Parkinsonism

2021 ◽  
pp. 1-26
Author(s):  
Giulietta M. Riboldi ◽  
Emanuele Frattini ◽  
Edoardo Monfrini ◽  
Steven J. Frucht ◽  
Alessio Di Fonzo
Keyword(s):  
Differential Diagnosis ◽  
Early Onset ◽  
Clinical Presentation ◽  
Late Onset ◽  
Correct Diagnosis ◽  
Disease Onset ◽  
Practical Approach ◽  
Juvenile Onset ◽  
Laboratory Findings ◽  
Work Planning

Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson’s disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.

Abstract 19687: Morphological and Clinical Characteristics of Late and Young Age Onset Apical Hypertrophic Cardiomyopathy: Insight from a 13-Year Registry of Hypertrophic Cardomyopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hyemoon Chung ◽  
Geu-Ru Hong ◽  
Jungwoo Son ◽  
In-Jeong Cho ◽  
Chi Young Shim ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Early Onset ◽  
Clinical Characteristics ◽  
Late Onset ◽  
Disease Onset ◽  
Apical Hypertrophic Cardiomyopathy ◽  
Group A ◽  
Group B ◽  
Onset Group ◽  
Lv Diastolic Function

Background: Apical hypertrophic cardiomyopathy (ApHCM) might have different morphological and clinical features according to the age of disease onset, probably result from the distinct mechanism of pathogenesis. The aim of this study was to evaluated the morphological and clinical differences according to the age of disease onset in patients with ApHCM. Methods: This was a retrospective, observational study of 56 ApHCM patients (31 males, mean 65±9 years). Among 426 patients with diagnosed ApHCM from 2000 until 2013, we selected 56 patients who met the inclusion criteria: [[Unable to Display Character: &#9332;]] patiens who diagnosed with ApHCM before 60 years old and current age >60 years old, (group A, early onset, n=16); and [[Unable to Display Character: &#9333;]] who diagnosed with ApHCM after 60 years old who had no evidence of apical hypertrophy confirmed by previous echocardiography (group B, late onset, n=40). Morphological LV feature was assessed by transthoracic echocardiography, which were divided into pure and mixed type. Furthermore, hemodynamic parameters and clinical events were also evaluated. Results: There were no differences in the presence of hypertension, LV systolic function and left atrial volume index between group A and B. However, early onset group A had more increased maximal wall thickness of LV apex (17.08±2.02 vs 15.43±1.68mm, p=0.005), and more incidence of pure type (100% (16/16) vs 56.8% (21/40), p=0.001) compare than late onset group B. Group B had older age (65±5 vs 72±4 years, p=0.001), increased LV end-diastolic dimension (51.25±2.32 vs 48.58±3.37mm, p=0.006), increased E/E’ (11.24±2.94 vs 14.60±6.37, p=0.049) with decreased E’ (5.61±1.34 vs 4.66±1.38cm/s, p=0.024) respectively.There were no significant differences in the risk of cardiovascular complication such as atrial fibrillation and stoke between group A and B. Conclusions: There was obvious different clinical characteristics according to the age of disease onset. Early onset ApHCM has typical morphological feature and relatively preserved LV diastolic function, compared with late onset ApHCM. Our result supports that late onset ApHCM was related to decreased LV diastolic function and increased LV wall thickness, which reflects the potential myocardial remodeling with aging.

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