New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Masked speech recognition and reading in children (Miller et al., 2018)

<div><b>Purpose: </b>The relationship between reading (decoding) skills, phonological processing abilities, and masked speech recognition in typically developing children was explored. This experiment was designed to evaluate the relationship between phonological processing and decoding abilities and 2 aspects of masked speech recognition in typically developing children: (a) the ability to benefit from temporal and spectral modulations within a noise masker and (b) the masking exerted by a speech masker.</div><div><b>Method:</b> Forty-two typically developing 3rd- and 4th-grade children with normal hearing, ranging in age from 8;10 to 10;6 years (mean age = 9;2 years, <i>SD</i> = 0.5 months), completed sentence recognition testing in 4 different maskers: steady-state noise, temporally modulated noise, spectrally modulated noise, and two-talker speech. Children also underwent assessment of phonological processing abilities and assessments of single-word decoding. As a comparison group, 15 adults with normal hearing also completed speech-in-noise testing.</div><div><b>Results: </b>Speech recognition thresholds varied between approximately 3 and 7 dB across children, depending on the masker condition. Compared to adults, performance in the 2-talker masker was relatively consistent across children. Furthermore, decreasing the signal-to-noise ratio had a more precipitously deleterious effect on children’s speech recognition in the 2-talker masker than was observed for adults. For children, individual differences in speech recognition threshold were not predicted by phonological awareness or decoding ability in any masker condition.</div><div><b>Conclusions: </b>No relationship was found between phonological awareness and/or decoding ability and a child’s ability to benefit from spectral or temporal modulations. In addition, phonological awareness and/or decoding ability was not related to speech recognition in a 2-talker masker. Last, these data suggest that the between-listeners variability often observed in 2-talker maskers for adults may be smaller for children. The reasons for this child–adult difference need to be further explored.</div><div><br></div><div><b>Supplemental Material S1. </b>Phonological processing/reading measures: children (ordering of data is consistent across Supplemental Materials S2 and S4). </div><div><br></div><div><b>Supplemental Material S2.</b> Masker condition signal recognition thresholds (SRTs, dB SNR) in children (ordering of data is consistent across Supplemental Materials S1 and S4). </div><div><br></div><div><b>Supplemental Material S3.</b> Masker condition signal recognition thresholds (SRTs, dB SNR) in adults (ordering of data is consistent with Supplemental Material S5). </div><div><br></div><div><b>Supplemental Material S4.</b> Masker condition signal recognition slopes in children (ordering of data is consistent across Supplemental Materials S1 and S2). </div><div><br></div><div><b>Supplemental Material S5.</b> Masker condition signal recognition slopes in adults (ordering of data is consistent with Supplemental Material S3). </div><div><br></div><div><b>Supplemental Material S6.</b> Least-squares (LS) means estimates of masker condition signal recognition thresholds (SRTs) in adults and children. </div><div><br></div><div><b>Supplemental Material S7.</b> Least-squares (LS) means estimates of masker condition signal recognition slopes in adults and children. </div><div><br></div><div><b>Supplemental Material S8.</b> Two-talker masker speech recognition threshold (SRT) regression results: children. </div><div><b><br></b></div><div><b>Supplemental Material S9.</b> Spectral modulation benefit regression results: children.</div><div><br></div><div><b>Supplemental Material S10. </b>Amplitude modulation benefit regression results: children.</div><div><br></div><div><b>Supplemental Material S11.</b> Steady-state noise slope regression results: children. </div><div><br></div><div>Miller, G., Lewis, B., Benchek, P., Buss, E., & Calandruccio, L. (2018). Masked speech recognition and reading ability in school-age children: Is there a relationship? <i>Journal of Speech, Language, and Hearing Research, 61, </i>776–788<i>.</i> https://doi.org/10.1044/2017_JSLHR-H-17-0279</div

Hadoop and PySpark for reproducibility and scalability of genomic sequencing studies

Modern genomic studies are rapidly growing in scale, and the analytical approaches used to analyze genomic data are increasing in complexity. Genomic data management poses logistic and computational challenges, and analyses are increasingly reliant on genomic annotation resources that create their own data management and versioning issues. As a result, genomic datasets are increasingly handled in ways that limit the rigor and reproducibility of many analyses. In this work, we examine the use of the Spark infrastructure for the management, access, and analysis of genomic data in comparison to traditional genomic workflows on typical cluster environments. We validate the framework by reproducing previously published results from the Alzheimer's Disease Sequencing Project. Using the framework and analyses designed using Jupyter notebooks, Spark provides improved workflows, reduces user-driven data partitioning, and enhances the portability and reproducibility of distributed analyses required for large-scale genomic studies

Ancestry‐Specific eQTL Associations in AA/NHW Alzheimer Disease Cohorts

Background Although the genetic etiology of Alzheimer’s Disease (AD) has been shown to vary among ancestrally diverse populations, the influence of genetic variation on the transcriptome within these populations has not yet been extensively investigated. Multi‐ancestry AD datasets featuring both genetic information and gene expression measurements are needed to support expression quantitative trait loci (eQTl) studies in historically underrepresented populations. In this work, we have compared eQTL signals in case/control AD sample populations of both African American (AA) and non‐Hispanic white (NHW) ancestries. Method We analyzed cohorts of AA and NHW ancestries (Naa = 232, Nnhw = 241) with corresponding array‐based genotypes and RNA‐seq mRNA expression levels from whole blood, along with clinical AD diagnoses (Naa_case = 115, Naa_control = 117, Nnhw_case = 121, Nnhw_control = 120). Transcriptome‐wide eQTL associations between genetic variants and gene expression levels were assessed via regression across 17,638 gene units, adjusting for age, sex, experimental factors, and genetic principal components. This was repeated across all sample set combinations of ancestry‐AD pairings (ancestry = [aa, nhw, both] * AD = [case, control, both]). Result The number of significant (p‐value < 10e‐7) eQTL signals varied by ancestry, with the AA cohort showing 76,742 raw eQTL associations, the NHW cohort 19,734, and both ancestries combined 81,763. When further sub‐setting sample sets to AD cases only, 770 and 788 significant eQTL signals were observed for AA and NHW cohorts respectively, which impacted 135 (AA) and 130 (NHW) genes. Interestingly, these ancestry‐aware, case‐only eQTLs were remarkably distinct between the two ancestries, with only 71 (∼9.1%) of the eQTLs and only 19 (∼14.3%) of the impacted genes being shared by both ancestral cohorts. Of particular interest is the appearance of WWOX (a gene of wide neurological importance, and known AD risk loci), as differentially significant in the AA cohort (P = 8.07e‐7) as compared to the NHW cohort (P = 9.06e‐3). Conclusion We have observed differences in eQTL signals relative to AD diagnosis status between AA and NHW sample populations, which may indicate the presence of novel ancestry‐specific effects impacting the genetic etiology of AD through changes in gene expression

Mycobacterium tuberculosis-dependent monocyte expression quantitative trait loci, cytokine production, and TB pathogenesis

IntroductionThe heterogeneity of outcomes after Mycobacterium tuberculosis (Mtb) exposure is a conundrum associated with millennia of host-pathogen co-evolution. We hypothesized that human myeloid cells contain genetically encoded, Mtb-specific responses that regulate critical steps in tuberculosis (TB) pathogenesis.MethodsWe mapped genome-wide expression quantitative trait loci (eQTLs) in Mtb-infected monocytes with RNAseq from 80 Ugandan household contacts of pulmonary TB cases to identify monocyte-specific, Mtb-dependent eQTLs and their association with cytokine expression and clinical resistance to tuberculin skin test (TST) and interferon-γ release assay (IGRA) conversion.Resultscis-eQTLs (n=1,567) were identified in Mtb-infected monocytes (FDR&lt;0.01), including 29 eQTLs in 16 genes which were Mtb-dependent (significant for Mtb:genotype interaction [FDR&lt;0.1], but not classified as eQTL in uninfected condition [FDR≥0.01]). A subset of eQTLs were associated with Mtb-induced cytokine expression (n=8) and/or clinical resistance to TST/IGRA conversion (n=1). Expression of BMP6, an Mtb-dependent eQTL gene, was associated with IFNB1 induction in Mtb-infected and DNA ligand-induced cells. Network and enrichment analyses identified fatty acid metabolism as a pathway associated with eQTL genes.DiscussionThese findings suggest that monocyte genes contain Mtb-dependent eQTLs, including a subset associated with cytokine expression and/or clinical resistance to TST/IGRA conversion, providing insight into immunogenetic pathways regulating susceptibility to Mtb infection and TB pathogenesis

Novel HLA associations with outcomes of Mycobacterium tuberculosis exposure and sarcoidosis in individuals of African ancestry using nearest-neighbor feature selection

Tuberculosis and sarcoidosis are inflammatory diseases characterized by granulomas that may occur in any organ but are often found in the lung. The panoply of classical human leukocyte antigen (HLA) alleles associated with occurrence and/or severity of both diseases varies considerably across studies. This heterogeneity of results, due to variation in factors like ancestry and disease subphenotype, as well as the use of simple modeling strategies to elucidate likely complex relationships, has made conclusions about underlying commonalities difficult. Here we perform HLA association analyses in individuals of African ancestry, using a greater resolution to include subphenotypes of disease and employing more comprehensive analytical techniques. Using a novel application of nearest-neighbor feature selection to score allelic importance, we investigated HLA allele association with Mycobacterium tuberculosis exposure outcomes in the first analysis of both latent Mycobacterium tuberculosis infection and active disease compared with those who, despite long-term exposure to active index cases, have neither positive diagnostic tests nor display clinical symptoms. We also compared persistent to resolved sarcoidosis. This led to the identification of novel HLA associations and evidence of main effects and interaction effects. We found strikingly similar main effects and interaction effects at HLA-DRB1, -DQB1, and -DPB1 in those resistant to tuberculosis (either latent or active) and persistent sarcoidosis

Individuals of African ancestry share HLA alleles protective against tuberculosis and sarcoidosis

Tuberculosis (TB) and sarcoidosis are distinct granulomatous disorders with numerous genetic associations. Human leukocyte antigen (HLA) is important in susceptibility and progression in both diseases. Although TB is caused by Mycobacterium tuberculosis, HLA associations in case control TB studies are highly variable, potentially due to phenotype heterogeneity, limited allelic resolution, and narrow analytical methods that exclude more complex associations common to biological data. Using four digit HLA alleles and applying more inclusive feature selection methodology, we provide the first HLA association analysis in TB that compares latent and active TB to individuals who display no evidence of infection and maintain negative diagnostic tests over a long term period of exposure to individuals with active TB. To detect a more comprehensive array of statistical effects, we introduce a novel application of nearest neighbor feature selection that uses a consensus approach across three input neighborhood algorithms to define allelic importance for classifying outcomes. This nearest neighbor approach is generally applicable in the context of binary classification and regression, with either categorical or continuous predictors. We compare our findings to sarcoidosis, both persistent and resolving. We provide the first comparison between TB and sarcoidosis resistance phenotypes, showing that HLA-DRB1 alleles ∗01:02, ∗03:02, ∗12:01, and ∗13:02 are associated with both resolving sarcoidosis in African Americans and long term resistance to latent or active TB in Ugandans

Association between genes regulating neural pathways for quantitative traits of speech and language disorders

Abstract Speech sound disorders (SSD) manifest as difficulties in phonological memory and awareness, oral motor function, language, vocabulary, reading, and spelling. Families enriched for SSD are rare, and typically display a cluster of deficits. We conducted a genome-wide association study (GWAS) in 435 children from 148 families in the Cleveland Family Speech and Reading study (CFSRS), examining 16 variables representing 6 domains. Replication was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 18 significant loci (combined p < 10−8) that we pursued bioinformatically. We prioritized 5 novel gene regions with likely functional repercussions on neural pathways, including those which colocalized with differentially methylated regions in our sample. Polygenic risk scores for receptive language, expressive vocabulary, phonological awareness, phonological memory, spelling, and reading decoding associated with increasing clinical severity. In summary, neural-genetic influence on SSD is primarily multigenic and acts on genomic regulatory elements, similar to other neurodevelopmental disorders

Low Back and Common Widespread Pain Share Common Genetic Determinants

Low back (LBP) and chronic widespread musculoskeletal pain (CWP) both have a significant genetic component and are associated with increased body mass index (BMI). We examined whether LBP and CWP share common genetic factors, and to what extent this correlation is modified by the genetic factors influencing BMI. Genetic analysis of binary traits such as pain is not simple, particularly if their risk is associated with age or other quantitative traits. Implementing Falconer's polygenic threshold concept for dichotomous traits inheritance, we developed new software to examine the extent of the genetic influence on LBP and CWP under age and BMI dependence. The analysis was conducted on 3266 and 2256 UK female twins, assessed for LBP and CWP, respectively. Analysis of the liability scores with threshold to LBP and CWP established substantial contribution of genetic factors to their variation (h(2) > 0.60,