Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

IMPORTANCE Some of the unexplained heritability of Alzheimer disease (AD) may be due to rare variants whose effects are not captured in genome-wide association studies because very large samples are needed to observe statistically significant associations. OBJECTIVE To identify genetic variants associated with AD risk using a nonstatistical approach. DESIGN, SETTING, AND PARTICIPANTS Genetic association study in which rare variants were identified by whole-exome sequencing in unrelated individuals of European ancestry from the Alzheimer’s Disease Sequencing Project (ADSP). Data were analyzed between March 2017 and September 2018. MAIN OUTCOMES AND MEASURES Minor alleles genome-wide and in 95 genes previously associated with AD, AD-related traits, or other dementias were tabulated and filtered for predicted functional impact and occurrence in participants with AD but not controls. Support for several findings was sought in a whole-exome sequencing data set comprising 19 affected relative pairs from Utah high-risk pedigrees and whole-genome sequencing data sets from the ADSP and Alzheimer’s Disease Neuroimaging Initiative. RESULTS Among 5617 participants with AD (3202 [57.0%] women; mean [SD] age, 76.4 [9.3] years) and 4594 controls (2719 [59.0%] women; mean [SD] age, 86.5 [4.5] years), a total of 24 variants with moderate or high functional impact from 19 genes were observed in 10 or more participants with AD but not in controls. These variants included a missense mutation (rs149307620 [p.A284T], n = 10) in NOTCH3, a gene in which coding mutations are associated with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), that was also identified in 1 participant with AD and 1 participant with mild cognitive impairment in the whole genome sequencing data sets. Four participants with AD carried the TREM2 rs104894002 (p.Q33X) high-impact mutation that, in homozygous form, causes Nasu-Hakola disease, a rare disorder characterized by early-onset dementia and multifocal bone cysts, suggesting an intermediate inheritance model for the mutation. Compared with controls, participants with AD had a significantly higher burden of deleterious rare coding variants in dementia-associated genes (2314 vs 3354 cumulative variants, respectively; P = .006). CONCLUSIONS AND RELEVANCE Different mutations in the same gene or variable dose of a mutation may be associated with result in distinct dementias. These findings suggest that minor differences in the structure or amount of protein may be associated with in different clinical outcomes. Understanding these genotype-phenotype associations may provide further insight into the pathogenic nature of the mutations, as well as offer clues for developing new therapeutic targets

Analysis of High-Risk Pedigrees Identifies 12 Candidate Variants for Alzheimer\u27s Disease

INTRODUCTION: Analysis of sequence data in high-risk pedigrees is a powerful approach to detect rare predisposition variants. METHODS: Rare, shared candidate predisposition variants were identified from exome sequencing 19 Alzheimer\u27s disease (AD)-affected cousin pairs selected from high-risk pedigrees. Variants were further prioritized by risk association in various external datasets. Candidate variants emerging from these analyses were tested for co-segregation to additional affected relatives of the original sequenced pedigree members. RESULTS: AD-affected high-risk cousin pairs contained 564 shared rare variants. Eleven variants spanning 10 genes were prioritized in external datasets: rs201665195 (ABCA7), and rs28933981 (TTR) were previously implicated in AD pathology; rs141402160 (NOTCH3) and rs140914494 (NOTCH3) were previously reported; rs200290640 (PIDD1) and rs199752248 (PIDD1) were present in more than one cousin pair; rs61729902 (SNAP91), rs140129800 (COX6A2, AC026471), and rs191804178 (MUC16) were not present in a longevity cohort; and rs148294193 (PELI3) and rs147599881 (FCHO1) approached significance from analysis of AD-related phenotypes. Three variants were validated via evidence of co-segregation to additional relatives (PELI3, ABCA7, and SNAP91). DISCUSSION: These analyses support ABCA7 and TTR as AD risk genes, expand on previously reported NOTCH3 variant identification, and prioritize seven additional candidate variants

The Opioid Abuse Risk Screener predicts aberrant same-day urine drug tests and 1-year controlled substance database checks: A brief report

The Opioid Abuse Risk Screener was developed to support well-informed decision-making in opioid analgesic prescribing by extending the breadth of psychiatric risk factors evaluated relative to other non–clinician-administered measures. We examined the preliminary predictive validity of the Opioid Abuse Risk Screener relative to the widely used Screener and Opioid Assessment for Patients with Pain–Revised in predicting aberrant urine drug tests and controlled substance database checks. The Opioid Abuse Risk Screener is significantly different from the Screener and Opioid Assessment for Patients with Pain–Revised in predicting aberrant same-day urine drug tests ( Z  = 2.912, p  = 0.0036) and controlled substance database checks within 1 year of assessment ( Z  = 3.731, p  = 0.0002). Promising preliminary analyses using machine learning methods are also discussed

Additional file 10: of Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels

File contains a Q-Q plot of the CSF in the Knight ADRC samples. (DOCX 52 kb

Additional file 4: of Genome-wide association study of prolactin levels in blood plasma and cerebrospinal fluid

File contains a Q-Q plot of the CSF data used in this study. (DOCX 76 kb

Saxifraga cherlerioides D. Don var. rebunshirensis Hara

原著和名: シコタンサウ科名: ユキノシタ科 = Saxifragaceae採集地: 長野県 八ヶ岳麓 (信濃 八ヶ岳麓)採集日: 1953/7/12採集者: 萩庭丈壽整理番号: JH046163国立科学博物館整理番号: TNS-VS-99616

Additional file 3: of Genome-wide association study of prolactin levels in blood plasma and cerebrospinal fluid

File contains a Q-Q plot of the plasma data used in this study. (DOCX 74 kb

Myoporum boninense Koidz.

原著和名: コハマヂンチャウ科名: ハマジンチョウ科 = Myoporaceae採集地: 東京都 小笠原村 父島 (小笠原村 父島)採集日: 1970/6/22採集者: 萩庭丈壽整理番号: JH045418国立科学博物館整理番号: TNS-VS-99541

Identification and genomic analysis of pedigrees with exceptional longevity identifies candidate rare variants

BackgroundLongevity as a phenotype entails living longer than average and typically includes living without chronic age-related diseases. Recently, several common genetic components to longevity have been identified. This study aims to identify additional genetic variants associated with longevity using unique and powerful analyses of pedigrees with a statistical excess of healthy elderly individuals identified in the Utah Population Database (UPDB).MethodsFrom an existing biorepository of Utah pedigrees, six independent cousin pairs were selected from four extended pedigrees that exhibited an excess of healthy elderly individuals; whole exome sequencing (WES) was performed on two elderly individuals from each pedigree who were either first cousins or first cousins once removed. Rare (<.01 population frequency) variants shared by at least one elderly cousin pair in a region likely to be identical by descent were identified as candidates. Ingenuity Variant Analysis was used to prioritize putative causal variants based on quality control, frequency, and gain or loss of function. The variant frequency was compared in healthy cohorts and in an Alzheimer's disease cohort. Remaining variants were filtered based on their presence in genes reported to have an effect on the aging process, aging of cells, or the longevity process. Validation of these candidate variants included tests of segregation on other elderly relatives.ResultsFifteen rare candidate genetic variants spanning 17 genes shared within cousins were identified as having passed prioritization criteria. Of those variants, six were present in genes that are known or predicted to affect the aging process: rs78408340 (PAM), rs112892337 (ZFAT), rs61737629 (ESPL1), rs141903485 (CEBPE), rs144369314 (UTP4), and rs61753103 (NUP88 and RABEP1). ESPL1 rs61737629 and CEBPE rs141903485 show additional evidence of segregation with longevity in expanded pedigree analyses (p-values = .001 and .0001, respectively).DiscussionThis unique pedigree analysis efficiently identified several novel rare candidate variants that may affect the aging process and added support to seven genes that likely contribute to longevity. Further analyses showed evidence for segregation for two rare variants, ESPL1 rs61737629 and CEBPE rs141903485, in the original longevity pedigrees in which they were initially observed. These candidate genes and variants warrant further investigation