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Background: Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur in each sex. Method: We created the MIAMI‐AD, a comprehensive database containing manually curated summary statistics from 97 published tables in 37 studies, all of which included at least 100 participants. There are four main sections: Genome‐wide Query, Gene Query, CpG Query, and Epigenetic Clock Query. Result: MIAMI‐AD enables easy browsing, querying, and downloading DNAm associations at multiple levels – at individual CpG, gene, genomic regions, or genome‐wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI‐AD facilitates our understanding of age‐associated CpGs in AD and in revealing sex‐specific DNAm differences in AD. Conclusion: MIAMI‐AD (https://miami‐ad.org/) facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. This open‐access resource is freely available to the research community, and all the underlying data can be downloaded. [ABSTRACT FROM AUTHOR]

Myopia is by far the most common human eye disorder that is known to have a clear, albeit poorly defined, heritable component. In this study, we describe an autosomal-recessive syndrome [...]

Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor. Rett syndrome | Y box-binding protein 1

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention. Author summary: Strong associations between ApoE ε4 and Alzheimer disease risk have been confirmed worldwide, but there is variability in the effect size across populations. African-descent populations have a lower risk from ApoE ε4 compared to other populations. Studies in admixed populations have shown that the African ancestral background surrounding the ApoE gene reduces the ε4 risk allele effect. Our objective in this study was to identify areas of the genome that interact with ApoE ε4 in African ancestry and result in a lower risk for developing Alzheimer disease. In this study we identify a protective locus for the ApoE ε4 allele that lowers the risk for African carriers of the ApoE ε4 allele to get Alzheimer disease from an odds ratio of 7.2 to 2.1. This protective haplotype has a frequency of 12% in the African ancestry, but only 0.003 in Europeans. This has been replicated in three independent African ancestry datasets and is trending in a much larger European dataset. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported that non‐Hispanic White (NHW) females carrying the APOE ε4 allele have an increased risk for developing AD when compared to men. Recently, analyses showed that the risk for developing AD may be equivalent for males and females but may differ by age. Few studies have been done on this issue in groups other than NHW. We aimed to evaluate the association between sex, age, ancestry, APOE, and AD. Methods: We conducted a pooled case‐control study from 45 independent databases in Alzheimer's Disease Genetics Consortium. Individuals (age≥55 years) were included (n = 31,058). Independent variables were age, sex, ancestry/ethnicity, and APOE genotype (ε3/ε4 vs. ε3/ε3). Logistic, linear, and Cox regression models were performed by sex and ancestry. Results: Regardless of ancestry, men and women with APOE ε3/ε4 showed no significant difference in the risk of developing AD (all age groups combined). When comparing subjects with APOE ε3/ε4 to those with ε3/ε3, East‐Asian (EA) females (OR,4.90; 95% CI: 3.46‐6.95) had the strongest OR, followed by EA males (OR, 4.09: 2.67‐6.27); and NHW females (OR,3.40: 3.14‐3.68) and men (OR,3.33: 3.03‐3.66) among all ethnicities. When stratified by age, NHW females (OR, 3.41: 2.69‐4.32 vs. NHW males: OR,2.57: 1.94‐3.39) and EA women (OR,6.51: 1.31‐32.30 vs. EA men: OR,3.41: 0.66‐17.56) with APOE ε3/ε4 showed a higher risk of developing AD between ages 55‐65; whereas African American (AA) women (OR,4.14: 3.06‐5.60 vs. AA men: OR,2.27: 1.45‐3.55) exhibited this pattern later, at the age of 66‐75 years. In Hispanics, the pattern is reversed, with males aged 55‐65 years carrying APOE ε3/ε4 (OR,6.65; 1.64‐26.89: vs. females: OR,2.27; 1.03‐4.98) had a stronger association with AD risk than their female counterpart. Case‐only and survival analyses also showed that NHW and EA female carriers of APOE ε3/ε4 had an earlier age at the onset of AD than their counterpart in men. Conclusions: Our findings suggest sex differences by age and ethnicity in the risk for developing AD and age at onset of AD for carriers of APOE ε4. Confirming these findings could lead to a better‐personalized risk assessment for AD that accounts for sex differences in APOE. [ABSTRACT FROM AUTHOR]

Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between Rai1 and social impairment, we evaluated the Rai1+/- mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that Rai1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients. [ABSTRACT FROM AUTHOR]