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

Infant-Parent Attachment and Parental and Child Behavior During Parent-Toddler Storybook Interaction

Longitudinal associations between infant-parent attachment and parental and toddler behavior during storybook interaction were examined for 131 lower-middle to middle-class families (70 girls; 61 boys). At ages 12 and 15 months, infant-mother and infant-father dyads were videotaped in the laboratory-based Strange Situation procedure to assess attachment. At 24 months, dyads visited the laboratory and were videotaped during storybook interaction. Infants with a history of insecure-resistant attachment with their mothers were less enthusiastic and focused during storybook interaction. Moreover, mothers of insecure-resistant infants were less warm and supportive, more hostile and intrusive, more detached, and less stimulating of cognitive development than mothers of secure or avoidant infants. Disorganized attachment did not predict the quality of storybook interaction and few attachment-related differences were found when the toddler-father dyad was considered

Young Children’s Self-Concepts: Associations with Child Temperament, Mothers’ and Fathers’ Parenting, and Triadic Family Interaction

This study explored how children’s self-concepts were related to child temperament, dyadic parenting behavior, and triadic family interaction. At age 3, child temperament, mothers’ and fathers’ parenting behavior, and triadic (mother, father, and child) family interaction were observed in the homes of 50 families. At age 4, children’s self-concepts were assessed using the Children’s Self-View Questionnaire (Eder, 1990). Analyses revealed that temperamental proneness to distress and triadic family interaction made independent contributions to children’s self-reported timidity and agreeableness. In contrast, dyadic parenting behavior moderated the associations between child temperament and children’s self-reported timidity and agreeableness such that temperament was only associated with children’s self-concepts when mothers and fathers engaged in particular parenting behaviors. Results suggest both direct and interactive influences of family dynamics and child characteristics on children’s self-concept development

Exploring Mothers’ and Fathers’ Reported Use of Discipline Practices With Their Preschoolers: Associations With Parental Well-Being

Supporting parents in use of effective, evidence-based discipline remains an important goal for research, practice, and policy. This study explored parental well-being and reported discipline practices with preschoolers (2–5 years). Parents (N = 205; 97 fathers) completed a Qualtrics-based survey assessing discipline practices, feelings of judgment in the parental role, anxiety and depression symptoms, and fear of happiness. Parents higher on anxiety used greater structure/limit setting. Higher parental anxiety and depression symptoms related to greater fear of happiness, and fathers higher on anxiety reported greater judgment in the parental role. For mothers, fear of happiness was modestly and positively associated with use of directive/punitive discipline and negatively associated with use of structure/limit setting. Results suggest parental well-being may be linked to discipline use in unique ways for mothers and fathers. Findings can support researchers and community professionals in understanding an array of parental characteristics that may relate to discipline practices

Parental personality, mental health, and fear of happiness as predictors of perceived coparenting relationship quality among mothers and fathers of preschoolers

Objective Existing theoretical models and research findings highlight individual parent characteristics as contributors to coparenting relationship quality. Yet less is known about how indices of parental personality, beliefs, and mental health symptoms relate to coparenting perceptions among parents of preschoolers. This study examines direct and indirect paths connecting parents’ Big Five personality traits, fear of happiness, and depression and anxiety symptoms with perceived coparenting quality. Method Using an online survey design, 160 parents (81 mothers; 79 fathers) of preschoolers (age 2–5 years) completed the Ten-Item Inventory of Personality, Fear of Happiness Scale, Patient Health Questionnaire-4, and Coparenting Relationship Scale – Brief Form. Results Parental Emotional Stability negatively related to anxiety and depressive symptoms and to fear of happiness. Anxiety symptoms and fear of happiness directly, and negatively, related to coparenting quality. Emotional stability was indirectly, positively related to coparenting quality via lower levels of parental anxiety and fear of happiness. Although parental depressive symptoms were unrelated to coparenting quality, parents’ Openness to Experience and fear of happiness positively predicted depressive symptoms. Conclusion Findings suggest parents’ anxiety symptoms and fear of happiness may underlie the processes by which parental Emotional Stability relates to perceived coparenting quality among parents of preschoolers

Environmental exposure assessment in European birth cohorts: results from the ENRIECO project

Environmental exposures during pregnancy and early life may have adverse health effects. Single birth cohort studies often lack statistical power to tease out such effects reliably. To improve the use of existing data and to facilitate collaboration among these studies, an inventory of the environmental exposure and health data in these studies was made as part of the ENRIECO (Environmental Health Risks in European Birth Cohorts) project. The focus with regard to exposure was on outdoor air pollution, water contamination, allergens and biological organisms, metals, pesticides, smoking and second hand tobacco smoke (SHS), persistent organic pollutants (POPs), noise, radiation, and occupational exposures. The review lists methods and data on environmental exposures in 37 European birth cohort studies. Most data is currently available for smoking and SHS (N=37 cohorts), occupational exposures (N=33), outdoor air pollution, and allergens and microbial agents (N=27). Exposure modeling is increasingly used for long-term air pollution exposure assessment; biomonitoring is used for assessment of exposure to metals, POPs and other chemicals; and environmental monitoring for house dust mite exposure assessment. Collaborative analyses with data from several birth cohorts have already been performed successfully for outdoor air pollution, water contamination, allergens, biological contaminants, molds, POPs and SHS. Key success factors for collaborative analyses are common definitions of main exposure and health variables. Our review emphasizes that such common definitions need ideally be arrived at in the study design phase. However, careful comparison of methods used in existing studies also offers excellent opportunities for collaborative analyses. Investigators can use this review to evaluate the potential for future collaborative analyses with respect to data availability and methods used in the different cohorts and to identify potential partners for a specific research question.This work was supported by ENRIECO (Environmental Health Risks in European Birth Cohorts), a project conducted within the European Union's 7th Framework Programme (Theme 6, Environment (Including Climate Change)) [Grant agreement number: 226285