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Background: African Americans (AA) are substantially underrepresented in Alzheimer's disease (AD) genetic studies, yet their admixed genetic ancestry (African and European) provides a unique opportunity to identify novel genetic factors associated with AD related to genetic ancestry. Admixture mapping (AM) provides a more powerful approach than SNP‐based genome‐wide association studies (GWAS) in admixed populations in part due to the lower multiple testing burden. In this study we used AM to identify regions associated with AD in AA individuals. Methods: Our analyses included 10,271 individuals from 17 AD Sequencing Project and AD Genetics Consortium cohorts. We estimated global ancestry (GA) using the GENESIS software. To infer local ancestry (LA), the target AA dataset was combined with appropriate reference‐population samples from HGDP reference panel, and LA was estimated using SHAPEIT followed by RFMix. Then, we performed AM using the GENESIS software separately on each cohort. We meta‐analyzed the AM results with the random effect approach (RE2). We calculated the significance threshold using STEAM software. Finally, we performed logistic regression of genotype on affection status for variants across the prioritized regions from AM for fine‐mapping. The regression model included LA and genotype as main effects and term for their interaction, along with GA, sex and age as covariates, and used permutation‐based testing approach for multiple test correction (N=10,000). Results: AM identified two genome‐wide significant loci on chromosomes 17p13.2 (pv=2.2 x10‐5) and 18q21.33 (pv=1.22x10‐5). 17p13.2 region was identified as a genome‐wide significant in two previous studies in non‐Hispanic White population. To fine map this region we conducted ancestry‐aware regression analysis. LA x genotype interaction model found the MINK1 gene (rs72835013) on the 17p13.2 region significantly associated with AD (pv = 1x10‐4). Conclusions: Our results confirmed an AD associated region on the chromosome 17p13.2 and showed that the 17p13.2 region increases AD risk in AA individuals with the European LA. This region includes genes previously indicated in AD such as SCIMP through association studies and the MINK1 and SLC25A11 genes through brain expression studies. [ABSTRACT FROM AUTHOR]

Background: Generalization of Alzheimer disease (AD) genetic findings to ancestrally admixed populations, such as African Americans (AA) and Caribbean Hispanics from Puerto Rico (PR), is challenging as they are underrepresented in most studies. There is evidence of differing underlying genetic architecture of AD in these groups, but identification of associated DNA variants is just a first step in understanding underlying biology. We evaluated the gene regulatory architecture by expression quantitative trait loci (eQTL) analysis within and across ancestries in a diverse cohort. Method: We performed RNAseq from peripheral blood and genotyping with the Illumina Global Screening Array in 537 individuals: 241 non‐Hispanic Whites (NHW) (121 AD, 120 cognitively intact controls), 232 AA (115 AD, 117 controls) and 64 PR (34 AD, 30 controls). All individuals had phenotypic adjudication for consensus AD status and were over the age of 65 at last examination and blood draw. We ran eQTL analysis overall and within each ancestry accounting for age and sex. Results were filtered for variant‐gene pairs with p‐values ≤ 1x10‐5. Result: We identified 1846 eQTLs at 737 genes, 2383 eQTLs at 791 genes, and 979 eQTLs in 459 genes in AA, NHW and PR, respectively. 603 eQTLs (∼30%) were significant across all ancestries with the same target gene and direction of effect. Interestingly, >70% of the PR eQTLs were also significant in either or both of the AA and NHW. Among eQTLs in linkage disequilibrium (r2>=0.5) with a significantly associated marker from AD GWAS studies in NHW (Kunkle at el 2019) or AA (Kunkle et all 2020) were two specific to AA for HLA‐DQB1 and C1QTNF4 and three to NHW for C2, CNN2, and PILRB. Analysis of case and control eQTL effects and the role of local ancestry in other admixed populations, including those with Amerindian ancestry, is ongoing. Conclusion: AA, NHW, and PR individuals have overlapping regulatory architecture that likely reflects the admixture in AA (20% European, 80% African) and PR (∼60% European, 20% African, and 20% Amerindian). These results underscore the importance of continuing to include diverse populations in AD genomics and functional studies to identify unique and shared architecture of AD. [ABSTRACT FROM AUTHOR]

Background: The ADSP‐FUS is a National Institute on Aging (NIA) initiative focused on identifying genetic risk and protective variants for late‐onset Alzheimer Disease (LOAD). A concern in AD genetic studies is a lack of racial‐ethnic diversity. The ADSP‐FUS collects and sequences existing ethnically diverse and unique cohorts with clinical data to expand the utility of new discoveries for individuals from all populations. Additional multi‐ethnic cohorts are presently being recruited (e.g., Amerindian, Asian and Indian). Method: The cohorts consist of participants from studies of AD, dementia, and aging‐related conditions. Clinical classification (i.e., AD, dementia, and non‐affected) is implemented using algorithms based on a minimal set of criteria derived from standard measures (e.g., global cognitive screeners, dementia rating scales, etc.) and clinical history. Data dictionaries are curated for each cohort by the FUS clinical staff. In total, the ADSP‐FUS intends to sequence over 60,000 individuals. Biospecimens are processed and DNA is prepared and allocated through the National Centralized Repository for Alzheimer's (NCRAD). The DNA is delivered to the Uniformed Services University of the Health Sciences (USUHS) for whole genome sequencing (WGS). The resulting raw sequence data is conveyed to the Genome Center for Alzheimer's Disease (GCAD) for processing and harmonization followed QC analysis at University of Pennsylvania and University of Miami resulting in analysis‐ready genotype data. Lastly, all clinical, genotype and sequence data are sent to the NIA Genetics of Alzheimer Disease Data Storage Site (NIAGADS), serving as the ASDP‐FUS data storage, management and sharing center. Results: Over 60,000 samples have been ascertained and are distributed by ancestry as follows: 7,686 African; 9,652 Hispanic; 40,575 non‐Hispanic white (1,400 EOAD and 3,745 autopsy); 89 Amerindian; 4,003 Asian and 2,000 Indian. To date, we have sequenced 8,208 NHW; 5,528 African; 6,149 Hispanic & 89 Amerindian. Conclusion: The ADSP‐FUS will enhance ongoing efforts to identify shared and novel genetic risk factors for LOAD among different populations. This project will expand our knowledge of potential genetic risk and protective variants for LOAD across all populations with the hope of developing new treatments that work for everyone. [ABSTRACT FROM AUTHOR]

Background: Genetic studies in Alzheimer disease (AD) are underrepresented in African‐descent populations. The African American (AA),population, with the admixed genetic ancestry (African and European) and high African ancestral background (∼80%), provides a unique opportunity to discover African ancestry‐specific genetic factors in AD. Admixture mapping (AM) is a powerful approach for genetic mapping of complex disease in admixed populations. AM uses local ancestry estimates to identify the genetic regions of specific ancestral origins (African, and European) that are associated with AD. These regions are likely to contain risk or protective genes for AD, and identifying these regions will inform sequence analysis in these and additional datasets. Methods: Analyses included 9050 individuals from 16 ADSP and ADGC cohorts We estimated and inferred global ancestry using the GENESIS software that provides robust inference of genetic ancestry in the presence of known and/or cryptic relatedness. To infer local ancestry the target AA dataset was combined with appropriate reference population samples from HGDP reference panel. Local ancestry was estimated using SHAPEIT followed by RFMix. We performed AM using the GENESIS software separately on 16 different cohorts. To meta‐analyse the admixture mapping results we developed in‐house scripts to align the ancestral blocks across cohorts. We used the METAL software for meta‐analysis and STEAM software to estimate the significance threshold. Results: We estimated significant threshold for admixture mapping analysis in AA dataset as 7.3e‐5 using analytic approximation approach from the STEAM package. The most significant region from the meta‐analysis was found on chromosome 4p16.3 (p‐value = 1.4e‐4) failed to reach genome‐wide significance. However, n two individual cohorts ADC8 (sample size = 850) and ADGC‐CHOP (sample size = 2,869) two regions showed genome‐wide significant association with disease on chromosome 18q21.33 (p‐value = 1.2e‐6) and chromosome 19p13.3 (p‐value<2.1e‐5), respectively. Conclusion: Our results confirm association of AD with the known ABCA7 genetic region on chromosome 19p13.3 through AM and suggest a genetic region for AD in AA population on 18q21.33; however, findings were not consistent across cohorts. We are in the process of analyzing data from additional AA cohorts to increase the power and allow us to dissect heterogeneity of AD in AA population. [ABSTRACT FROM AUTHOR]

There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B 's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale. • Genome-wide significant linkage (HLOD=3.3) on chr5q35 found in 9 AA AD families. • Rare regulatory variants for INSYN2B identified to segregate with AD in AA families. • Diversifying family-based design and WGS analyses crucial to understand AD globally. [ABSTRACT FROM AUTHOR]

A missense variant in the tetratricopeptide repeat domain 3 (TTC3) gene (rs377155188, p.S1038C, NM_003316.4:c 0.3113C>G) was found to segregate with disease in a multigenerational family with late-onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing, and the resulting isogenic pair of iPSC lines was differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3-dimensional morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant. [ABSTRACT FROM AUTHOR]

Background: Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. Methods: GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. Results: Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. Conclusions: As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. [ABSTRACT FROM AUTHOR]

• A genome-wide significant linkage peak (HLOD=5.1) on 9p21 was found in PR Families for AD. • A rare missense variant in UNC13B segregates within PR families and is associated with AD risk in an independent case-control PR WGS dataset. • Our study demonstrated the importance of family-based design and WGS in genetic study of AD. The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72 , but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD. [ABSTRACT FROM AUTHOR]

Standard procedures for measuring Alzheimer's disease (AD) plasma biomarkers include storage at -80°C. This is challenging in countries lacking research infrastructure, such -80°C freezer. To investigate stability of AD biomarkers from plasma stored at -20°C, we compared aliquots stored at -80°C and others at -20°C for two, four, six, fifteen, and thirty-five weeks. pTau181, Aβ42, Aβ40, NfL, and GFAP were measured for each timepoint. pTau181 and Aβ42/Aβ40 ratios showed minimal variation for up to 15 weeks. NfL and GFAP had higher variability. This finding of 15-week stability at -20°C enables greater participation in AD biomarker studies in resource constrained environments.

Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.

A missense variant in the tetratricopeptide repeat domain 3 ( TTC3 ) gene (rs377155188, p.S1038C, NM&#95;003316.4:c.3113C>G) was found to segregate with disease in a multigenerational family with late onset Alzheimer's disease. This variant was introduced into induced pluripotent stem cells (iPSCs) derived from a cognitively intact individual using CRISPR genome editing and the resulting isogenic pair of iPSC lines were differentiated into cortical neurons. Transcriptome analysis showed an enrichment for genes involved in axon guidance, regulation of actin cytoskeleton, and GABAergic synapse. Functional analysis showed that the TTC3 p.S1038C iPSC-derived neuronal progenitor cells had altered 3D morphology and increased migration, while the corresponding neurons had longer neurites, increased branch points, and altered expression levels of synaptic proteins. Pharmacological treatment with small molecules that target the actin cytoskeleton could revert many of these cellular phenotypes, suggesting a central role for actin in mediating the cellular phenotypes associated with the TTC3 p.S1038C variant., Highlights: The AD risk variant TTC3 p.S1038C reduces the expression levels of TTC3 The variant modifies the expression of AD specific genes BACE1 , INPP5F , and UNC5C Neurons with the variant are enriched for genes in the PI3K-Akt pathwayiPSC-derived neurons with the alteration have increased neurite length and branchingThe variant interferes with actin cytoskeleton and is ameliorated by Cytochalasin D.

Introduction: Studies of cognitive impairment (CI) in Amish communities have identified sibships containing CI and cognitively unimpaired (CU) individuals. We hypothesize that CU individuals may carry protective alleles delaying age at onset (AAO) of CI., Methods: A total of 1522 individuals screened for CI were genotyped. The outcome studied was AAO for CI individuals or age at last normal exam for CU individuals. Cox mixed-effects models examined association between age and single nucleotide variants (SNVs)., Results: Three SNVs were significantly associated (P < 5 × 10 -8 ) with AAO on chromosomes 6 (rs14538074; hazard ratio [HR] = 3.35), 9 (rs534551495; HR = 2.82), and 17 (rs146729640; HR = 6.38). The chromosome 17 association was replicated in the independent National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease dataset., Discussion: The replicated genome-wide significant association with AAO on chromosome 17 is located in the SHISA6 gene, which is involved in post-synaptic transmission in the hippocampus and is a biologically plausible candidate gene for Alzheimer's disease., (© 2022 the Alzheimer's Association.)

Importance: Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD., Objective: To search for rare variants contributing to the risk for EOAD., Design, Setting, and Participants: In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016., Main Outcomes and Measures: Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively., Results: Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129)., Conclusions and Relevance: The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor ( SORL1 ) gene., Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations., Results: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking., Conclusions: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation.

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD., Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families., Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function., Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Background: Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism., Methods: As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members., Results: Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions., Conclusions: These results provide additional support for the role of rare structural variation in ASD.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD., Methods: We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set., Results: One SNP, rs17321050, in the transducin β-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 × 10-6) and joint analysis (P value = 4.53 × 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 × 10-3) and passed the replication threshold in the validation data set (P = 2.56 × 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis., Conclusions: TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk.