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

High school science fair: School location trends in student participation and experience.

The findings reported in this paper are based on surveys of U.S. high school students who registered and managed their science and engineering fair (SEF) projects through the online Scienteer website over the three years 2019/20, 2020/21, and 2021/22. Almost 2500 students completed surveys after finishing all their SEF competitions. We added a new question in 2019/20 to our on-going surveys asking the students whether their high school location was urban, suburban, or rural. We learned that overall, 74% of students participating in SEFs indicated that they were from suburban schools. Unexpectedly, very few SEF participants, less than 4%, indicated that they were from rural schools, even though national data show that more than 20% of high school students attend rural schools. Consistent with previous findings, Asian and Hispanic students indicated more successful SEF outcomes than Black and White students. However, whereas Asian students had the highest percentage of SEF participants from suburban vs. urban schools- 81% vs. 18%, Hispanic students had the most balanced representation of participants from suburban vs. urban schools- 55% vs. 39%. Differences in students' SEF experiences based on gender and ethnicity showed the same patterns regardless of school location. In the few items where we observed statistically significant (probability < .05) differences based on school location, students from suburban schools were marginally favored by only a few percentage points compared to students from urban schools. In conclusion, based on our surveys results most students participating in SEFs come from suburban schools, but students participating in SEFs and coming from urban schools have equivalent SEF experiences, and very few students participating in SEFs come from rural schools

High school science fair: Positive and negative outcomes.

The goal of our ongoing research is to identify strengths and weaknesses of high school level science fair and improvements that can help science educators make science fair a more effective, inclusive and equitable learning experience. In this paper, we confirm and extend our previous findings in several important ways. We added new questions to our anonymous and voluntary surveys to learn the extent to which students had an interest in science or engineering careers and if science fair participation increased their interest in science or engineering. And we surveyed a national rather than regional high school student group by incorporating our survey into the Scienteer online portal now used by Texas and some other states for science fair registration, parental consent, and project management. We learned that about ~60% of the more than 300 students in the national cohorts completing surveys in 2017 and 2018 said that they were interested in a career in science or engineering, and ~60% said that participating in science fair increased their interest in science or engineering. About two-thirds of the students were required to participate in science fair, and that requirement reduced the frequency of students who said that science fair increased their interest. In the worst case, ~10% of the students who said that they were not interested in a career in science or engineering and who were required to participate in science fair engaged in research misconduct (i.e., plagiarism and making up their results). Students' positive comments about competition in science fair focused on the competition incentive, whereas their positive comments about science fair that was non-competitive focused on learning about the scientific process and learning in general. We discuss the findings in the context of National Science Teaching Association guidance about voluntary science fair participation and begin to identify features of science fair practice consistent with increased student interest in the sciences or engineering

High school science fair and research integrity

<div><p>Research misconduct has become an important matter of concern in the scientific community. The extent to which such behavior occurs early in science education has received little attention. In the current study, using the web-based data collection program REDCap, we obtained responses to an anonymous and voluntary survey about science fair from 65 high school students who recently competed in the Dallas Regional Science and Engineering Fair and from 237 STEM-track, post-high school students (undergraduates, 1st year medical students, and 1st year biomedical graduate students) doing research at UT Southwestern Medical Center. Of the post-high school students, 24% had competed in science fair during their high school education. Science fair experience was similar overall for the local cohort of Dallas regional students and the more diverse state/national cohort of post-high school students. Only one student out of 122 reported research misconduct, in his case making up the data. Unexpectedly, post-high school students who did not participate in science fair anticipated that carrying out science fair would be much more difficult than actually was the case, and 22% of the post-high school students anticipated that science fair participants would resort to research misconduct to overcome obstacles. No gender-based differences between students’ science fair experiences or expectations were evident.</p></div

Type of science fair project and requirement.

<p>Type of science fair project and requirement.</p

Misconduct anticipated by 40 out of 180 PHSn students.

<p>Misconduct anticipated by 40 out of 180 PHSn students.</p