There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer’s disease (AD) related cognitive decline, and AD related neuropathological markers.Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=−0.500, p=0.009), episodic memory (β=−0.411, p=0.009) and working memory (β=−0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=−0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age.
Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoid receptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory. We tested SNP variants at the CNR1 gene in two independent samples—an unselected adolescent sample from Northern Finland, and a family-based sample of trios (an ADHD child and their parents). In addition to using the trios for association study, the parents (with and without ADHD) were used as an additional case/control sample of adults for association tests. ADHD and its co-morbid psychiatric disorders were examined. A significant association was detected for a SNP haplotype (C-G) with ADHD (P = 0.008). A sex by genotype interaction was observed as well with this haplotype posing a greater risk in males than females. An association of an alternative SNP haplotype in this gene was found for post-traumatic stress disorder (PTSD) (P = 0.04 for C-A, and P = 0.01 for C-G). These observations require replication, however, they suggest that the CNR1 gene may be a risk factor for ADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.
This study demonstrates the utility of the Social Responsiveness Scale quantitative endophenotype to detect autism-related genetic loci using quantitative behavioral information that may more closely relate to underlying genetic factors.
Current genomewide association studies account for only a small fraction of the estimated heritabilities of genetically complex neuropsychiatric disorders, indicating they are likely to result from the small effects of numerous predisposing variants, many of which have gone undetected. The statistical power to detect associations of common variants with small effects is increased by conducting joint association tests of a single nucleotide polymorphism (SNP), an additional risk factor (F), and their interaction. F can represent an environmental exposure, another genotype or any source of genetic heterogeneity. In case and control studies, logistic regression makes joint tests straightforward. This analytic method cannot be employed directly when SNP transmission tests are used to detect associations in parent/affected child trios and multiplex families. However, the method can be implemented using the case/pseudocontrol approach. We applied this approach to analyze data from a genomewide association study of multiplex families ascertained for Autism Spectrum Disorder, where sex was used to define the F. Joint analyses revealed two associations exceeding genomewide significance. One novel gene, Ryandine Receptor 2, implicated in calcium channel defects, was identified with a joint P-value of 3.9E-11. Calcium channel defects have been connected to Autism spectrum disorder (ASD) by Timothy Syndrome, which is Mendelian, and a previous targeted sex-specific association analysis of idiopathic Autism. A second gene, uridine phosphorylase 2, with a joint P-value of 2.3E-9, has been previously linked and associated with Autism in independent samples. These findings highlight two Autism candidate genes for follow-up studies.
Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P < 0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P= 0.001, 0.001, 0.002), and one was intronic to KCND3 (P= 0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P= 0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.
In this population-based family study, ES is consistent with an autosomal dominant trait with incomplete penetrance, where the penetrance is more reduced in males than in females. However, the presence of ES was a greater risk factor for developing glaucoma in males than in females.
Abstract. Purpose: To estimate the prevalence of pseudoexfoliation syndrome or exfoliation syndrome (ES) in a cross‐sectional study and during a long‐term follow‐up, and to analyse how ES has been inherited in a large pedigree on an isolated population of Kökar island in southern Finland. Methods: In a population‐based study conducted between 1960 and 1962, a comprehensive ophthalmological examination was performed on 595 subjects (85% of the population). From then until 2002, 965 subjects were examined at least once. A pedigree was constructed for all ES‐affected subjects according to genealogical studies. The genetic contribution to ES was investigated in this pedigree by segregation analysis and the heritability of the intraocular pressure (IOP) quantitative trait estimated using SOLAR and SAGE software. Results: In the cross‐sectional study, the prevalence of ES was 8.1% for 247 subjects over 50 years of age (males 7%, females 9%) and increased to 18.4% for 70 subjects over 70 years of age (males 13%, females 25%). In addition, two females less than 50 years of age were ES‐affected. Between 1960 and 2002, 76 (14.3%) of 530 subjects over 50 years of age had ES [23 males (10%) and 53 females (18%)]. Exfoliation glaucoma (EG) was found more often in males (11 patients, 48%) than in females (13 patients, 25%) whereas primary open‐angle glaucoma (POAG) was almost as frequent in males (seven patients, 3%) as in females (five patients, 2%). The relative risk (RR) of glaucoma (ES versus no ES) was 11.9 [95% confidence interval (CI) 6.2–22.9] for all the subjects – 14.6 for males (95% CI 6.3–34.0) and 11.8 for females (95% CI 4.4–31.6). Seventy‐five pedigrees of 78 ES‐affected patients were linked together into one large pedigree with 110 nuclear families. The segregation ratio of ES was 18% (8% for males, 24% for females) when both parents were unaffected, and 16% (9% for males, 27% for females) when at least one parent was affected. The heritability of IOP was estimated to be 30%. Conclusion: In this population‐based family study, ES is consistent with an autosomal dominant trait with incomplete penetrance, where the penetrance is more reduced in males than in females. However, the presence of ES was a greater risk factor for developing glaucoma in males than in females.
Age-related changes to cytosine methylation have been extensively characterized across the mammalian family. Some cytosines that are conserved across mammals exhibit age-related methylation changes that are so consistent that they were used to successfully develop cross-species age predictors. In a similar vein, methylation levels of some conserved cytosines correlate highly with species lifespan, leading to the development of highly accurate lifespan predictors. Surprisingly, little to no commonality is found between these two sets of cytosines even though the relationship between aging and lifespan is by most measures linked. We ventured to address this conundrum by first identifying age-related cytosines whose methylation levels change in opposite directions between short and long-lived species. We hypothesized that age-related CpGs that are also associated with species lifespan would tap into biological processes that simultaneously impact aging and lifespan. To this end, we analyzed age-related cytosine methylation patterns in 82 mammalian species. For each CpG, we correlated the intra-species age correlation with maximum lifespan across mammalian species. We refer to this correlation of correlations as Lifespan Uber Correlation (LUC). This approach is unique in incorporating age and species lifespan in a single analysis. We identified 629 CpGs with opposing methylation aging patterns in long and short-lived species. Many of these are found to be near BCL11B, NPTN, and HOXC4 loci. Methylation and transcription analyses of Bcl11b knockout mice indicate that this gene partially regulates the methylation state of LUC CpGs. We developed DNAm age estimators (epigenetic clocks) based on LUC CpGs. These LUC clocks exhibited the expected behavior in benchmark aging interventions such as caloric restriction, growth hormone receptor knockout and high-fat diet. Furthermore, we found that Bcl11b heterozygous knockout mice exhibited an increased epigenetic age in the striatum. Overall, we present a bioinformatics approach that identified CpGs and their associated genes implicated both in aging and lifespan. These cytosines lend themselves to developing epigenetic clocks that are sensitive to perturbations that impact both age and lifespan.
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