Polygenic risk scores (PRS) are instrumental in genetics, offering insights into an individual level genetic risk to a range of diseases based on accumulated genetic variations. These scores rely on ...Genome-Wide Association Studies (GWAS). However, precision in PRS is often challenged by the requirement of extensive sample sizes and the potential for overlapping datasets that can inflate PRS calculations. In this study, we present a novel methodology, Meta-Reductive Approach (MRA), that was derived algebraically to adjust GWAS results, aiming to neutralize the influence of select cohorts. Our approach recalibrates summary statistics using algebraic derivations. Validating our technique with datasets from Alzheimer disease studies, we showed that the summary statistics of the MRA and those derived from individual-level data yielded the exact same values. This innovative method offers a promising avenue for enhancing the accuracy of PRS, especially when derived from meta-analyzed GWAS data.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ...ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10
), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10
), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10
). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
Mixed results in the predictive ability of traditional biomarkers to determine cognitive functioning and changes in older adults have led to misdiagnosis and inappropriate treatment plans to address ...mild cognitive impairment and dementia among older adults. To address this critical gap, the primary goal of the current study is to investigate whether a digital neuro signature (DNS-br) biomarker predicted global cognitive functioning and change over time relative among cognitively impaired and cognitive healthy older adults. The secondary goal is to compare the effect size of the DNS-br biomarker on global cognitive functioning compared to traditional imaging and genomic biomarkers. The tertiary goal is to investigate which demographic and clinical factors predicted DNS-br in cognitively impaired and cognitively healthy older adults.
We conducted two experiments (Study A and Study B) to assess DNS for brain resilience (DNS-br) against the established FDG-PET brain imaging signature for brain resilience, based on a 10 min digital cognitive assessment tool. Study A was a semi-naturalistic observational study that included 29 participants, age 65+, with mild to moderate mild cognitive impairment and AD diagnosis. Study B was also a semi-naturalistic observational multicenter study which included 496 participants (213 mild cognitive impairment (MCI) and 283 cognitively healthy controls (HC), a total of 525 participants-cognitively healthy (
= 283) or diagnosed with MCI (
= 213) or AD (
= 29).
DNS-br total score and majority of the 11 DNS-br neurocognitive subdomain scores were significantly associated with FDG-PET resilience signature, PIB ratio, cerebral gray matter and white matter volume after adjusting for multiple testing. DNS-br total score predicts cognitive impairment for the 80+ individuals in the Altoida large cohort study. We identified a significant interaction between the DNS-br total score and time, indicating that participants with higher DNS-br total score or FDG-PET in the resilience signature would show less cognitive decline over time.
Our findings highlight that a digital biomarker predicted cognitive functioning and change, which established biomarkers are unable to reliably do. Our findings also offer possible etiologies of MCI and AD, where education did not protect against cognitive decline.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non‐Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary ...by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood.
Methods
Self‐declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI‐Q) outcomes (NPI‐Q total score, NPI‐Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage.
Results
Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI‐Q total scores differed significantly between our groups, with HIW having the highest NPI‐Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI‐Q total score by sex. There were six NPI‐Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI‐Q items. Finally, Six NPI‐Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior.
Conclusions
We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.
Key points
Our study sought to determine if there are differences in neuropsychiatric symptom prevalence, as measured by the Neuropsychiatric Inventory Questionnaire (NPI‐Q), among self‐declared African American (AA), Hispanic, and Non‐Hispanic White (NHW) individuals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI).
While the prevalence of several NPI‐Q symptoms was consistent across the three groups our Hispanic participants showed a greater overall burden of neuropsychiatric symptoms—especially anxiety and mood symptoms (i.e., Anxiety, Depression, Apathy, and Irritability items). By contrast, African Americans reported significantly more behavioral problems as reflected on the Disinhibition and Elation items.
The variability in the prevalence of neuropsychiatric symptoms among different populations (e.g., mood and anxiety symptoms in HIW) represents both underlying genetic factors rooted in ancestral background as well as sociocultural influences on the measurement and reporting of NPS.
Introduction Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. Puerto Ricans (PR), a three-way admixed (European, African, and Amerindian) population is the ...second-largest Hispanic group in the continental US. We aimed to conduct a genome-wide association study (GWAS) and comprehensive analyses to identify novel AD susceptibility loci and characterize known AD genetic risk loci in the PR population. Materials and methods Our study included Whole Genome Sequencing (WGS) and phenotype data from 648 PR individuals (345 AD, 303 cognitively unimpaired). We used a generalized linear-mixed model adjusting for sex, age, population substructure, and genetic relationship matrix. To infer local ancestry, we merged the dataset with the HGDP/1000G reference panel. Subsequently, we conducted univariate admixture mapping (AM) analysis. Results We identified suggestive signals within the SLC38A1 and SCN8A genes on chromosome 12q13. This region overlaps with an area of linkage of AD in previous studies (12q13) in independent data sets further supporting. Univariate African AM analysis identified one suggestive ancestral block ( p = 7.2×10 −6 ) located in the same region. The ancestry-aware approach showed that this region has both European and African ancestral backgrounds and both contributing to the risk in this region. We also replicated 11 different known AD loci -including APOE - identified in mostly European studies, which is likely due to the high European background of the PR population. Conclusion PR GWAS and AM analysis identified a suggestive AD risk locus on chromosome 12, which includes the SLC38A1 and SCN8A genes. Our findings demonstrate the importance of designing GWAS and ancestry-aware approaches and including underrepresented populations in genetic studies of AD.
Background:
The Latino population is greatly understudied in biomedical research, including genetics. Very little information is available on presence of known variants originally identified in ...non-Hispanic white patients or novel variants in the Latino population. The Latino population is admixed, with contributions of European, African, and Amerindian ancestries. Therefore, the ancestry surrounding a gene (local ancestry, LA) can be any of the three contributing ancestries and thus can determine the presence or risk effect of variants detected.
Methods:
We sequenced the major exons and exons of reported Latino-specific variants in
GBA
and
LRRK2
and performed genome-wide genotyping for LA assessments in 79 Latino Parkinson disease (PD) patients, of which ~80% identified as Caribbean Latino.
Results:
We observed five carriers of LRRK2 p.G2019S, one GBA p.T408M, and three GBA p.N409S on European as well as three GBA p.L13R on African LA backgrounds. Previous Latino variant GBA p.K237E was not observed in this dataset. A novel highly conserved and predicted damaging variant LRRK2 p.D734N was identified in two unrelated individuals with African LA. Additionally, we identified rare, functional variants LRRK2 p.P1480L and GBA p.S310G in one individual each heterozygous for European/Amerindian LA.
Discussion:
Additional functional analysis will be needed to determine the pathogenicity of the novel variants in PD. However, the identification of novel disease variants in the Latino cohort potentially contributing to PD supports to importance of inclusion of Latinos in genetics research to provide insight in PD genetics in Latinos specifically as well as other populations with the same ancestral contributions.
Hearing loss (HL) is a common sensory disorder affecting over 5% of the global population. The etiology underlying HL includes congenital and acquired causes; genetic factors are the main cause in ...over 50% of congenital cases. Pathogenic variants in the
gene are a major cause of congenital non-syndromic hearing loss (NSHL), while their distribution is highly heterogeneous in different populations. To the best of our knowledge, there is no data regarding the genetic etiologies of HL in Peru. In this study, we screened 133 Peruvian families with NSHL living in Lima. We sequenced both exons of the
gene for all probands. Seven probands with familial NSHL that remained negative for
variants underwent whole genome sequencing (WGS). We identified biallelic pathogenic variants in
in 43 probands; seven were heterozygous for only one allele. The c.427C>T variant was the most common pathogenic variant followed by the c.35delG variant. WGS revealed three novel variants in
in two probands, one of them was predicted to affect splicing and the others produce a premature stop codon. The Peruvian population showed a complex profile for genetic variants in the
gene, this particular profile might be a consequence of the admixture history in Peru.
Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of ...AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer's Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations.
The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source.
We report on 674 individuals who met standard eligibility criteria 282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample). There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits.
The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.
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