Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Effects of Instruction on Preservice Elementary Teachers' Conceptions of the Causes of Night and Day and the Seasons

The purpose of this study was to test the effectiveness of brief instruction, based on Atwood and Atwood (1995, 1996), which addressed the causes of night and day and the seasons. 111c findings should be useful to science teacher educators who already are attempting to address these concepts as well as those who might choose to do so if the required time and resource commitments were shown to be modest

Fourth‐grade Elementary Students’ Conceptions of Standards‐based Lunar Concepts

Fourth-grade students’ knowledge of observable moon phases and patterns of change, as well as conceptual understanding of the cause of moon phases, was investigated before and after special instruction. Pretest and post-test data for 48 students were used to address the research question related to observable moon phases and patterns of change. Interviews were conducted with 10 students on a post-only basis to provide data on understanding the cause of moon phases. The researchers used the constant comparative method to analyse data. Pretest results indicate these students had not met the expectations expressed in the U.S. Science Education Standards for lunar concepts. Post-test results reveal a very positive performance on observable moon phases and patterns of change, as well as the cause of moon phases. Interpretation and implications of these findings are provided

Preservice elementary teachers' conceptions of moon phases before and after instruction

This study focused on the conceptual understandings held by 78 preservice elementary teachers about moon phases, before and after instruction. Participants in the physics groups received instruction on moon phases in an inquiry-based physics course; participants in the methods group received no instruction on moon phases. The instructive effect of two different types of preinstruction interviews also was compared. The instruction on moon phases used in the study is from Physics by Inquiry by Lillian McDermott. In the study, the method of inquiry followed a qualitative design, involving classroom observations, document analysis, and structured interviews. Inductive data analysis identified patterns and themes in the participants' conceptual understanding. Results indicate that without the instruction, most preservice teachers were likely to hold alternative conceptions on the cause of moon phases. Participants who had the instruction were much more likely to hold a scientific understanding after instruction. The instruction appears to be more effective in promoting a scientific understanding of moon phases than instruction previously reported in the literature. It also appears that using a three-dimensional model or making two-dimensional drawings during the preinstruction interviews does not have instructive value

A Longitudinal Study of Conceptual Change: Preservice Elementary Teachers’ Conceptions of Moon Phases

This research consists of a longitudinal study of 12 female elementary preservice teachers' conceptual understanding over the course of several months. The context in which the participants received instruction was in an inquiry-based physics course, and the targeted science content was the cause of moon phases. Qualitative research methods, including observations and interviews, were used to investigate and describe participants' conceptual understanding over time. Participants were interviewed on their understanding of the cause of moon phases before instruction, 3 weeks after instruction, and again in delayed post-interviews several months after instruction. Patterns and themes in the participants' conceptual understanding were identified through constant-comparative data analysis. Consistent with results reported earlier, participants who had instruction that included recording and analyzing moon observations over time and psychomotor modeling of changes in moon phases were very likely to hold a scientific conceptual understanding shortly after instruction. The present study indicates a majority of participants continued to hold a scientific understanding six months or more after instruction. However, some participants reverted to alternative conceptions they had shown during the pre-interview. These results are interpreted utilizing contemporary conceptual change theory

Preservice Elementary Teachers' Knowledge of Observable Moon Phases and Pattern of Change in Phases

The purpose of this study was to describe selected content knowledge held by 52 preservice elementary teachers about the observable phases of the moon and the monthly pattern of change in observable phases. Data were obtained from participants in a physics course before and after they received inquiry-based instruction designed to promote intentional learning of the cause of moon phases and the observable pattern of change in moon phases. Results indicated that, prior to instruction, most preservice teachers had major deficiencies in knowledge of observable moon phases and the pattern of monthly change in the phases. Fortunately, participants who completed the instruction were likely to show evidence of having addressed the deficiencies

The Effect of Guided Inquiry-Based Instruction on Middle School Students’ Understanding of Lunar Concepts

This study investigated the effect of non-traditional guided inquiry instruction on middle school students’ conceptual understandings of lunar concepts. Multiple data sources were used to describe participants’ conceptions of lunar phases and their cause, including drawings, interviews, and a lunar shapes card sort. The data were analyzed via a constant comparative method to produce profiles of each participant’s conceptual understandings and nonparametric tests also were used. Results revealed very positive performance for observable moon phases and patterns of change, as well as the cause of moon phases. Results indicated that significantly more participants shifted from drawing nonscientific shapes on the pretest to drawing scientific shapes on the post-test. Results for the drawings of moon phase sequences were similar in that significantly more participants shifted from drawing alternative waxing and waning sequences on the pretest to drawing scientific sequences on the post-test. Also, significantly more participants shifted from alternative understanding of the cause of the moon phases on the pretest to scientific understanding on the post-test. Implications of these findings and recommendations for further research are provided