IntroductionLate-onset Alzheimer's disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) [3][4][5][6][7][8] . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10 -7 ) indicating that additional rare variants remain to be identified. Main TextOur previous work identified 19 genome-wide significant common variant signals in addition to APOE 9 , that influence risk for LOAD. These signals, combined with 'subthreshold' common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 10 . To search for additional signals, we conducted a GWAS metaanalysis of non-Hispanic Whites (NHW) using a larger sample (17 new, 46 total datasets) from our group, the International Genomics of Alzheimer's Project (IGAP) (composed of four AD consortia: ADGC, CHARGE, EADI, and GERAD). This sample increases our previous discovery sample (Stage 1) by 29% for cases and 13% for controls (N=21,982 cases; 41,944 controls) ( Supplementary Table 1 and 2, and Supplementary Note). To sample both common and rare variants (minor allele frequency MAF ≥ 0.01, and MAF < 0.01, respectively), we imputed the discovery datasets using a 1000 Genomes reference panel consisting of . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a 11 36,648,992 single-nucleotide variants, 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis (a 63% increase from our previous common variant analysis in 2013).Genotype dosages were analyzed within each dataset, and then combined with meta-analysis ( Supplementary Figures 1 and 2 and Supplementary Table 3). The Stage 1 discovery metaanalysis was first followed by Stage 2 using the I-select chip we previously developed in Lambert et al (including 11,632 variants, N=18,845) and finally stage 3A (N=6,998). The final sample was 33,692 clinical AD cases and 56,077 controls.Meta-analysis of Stages 1 and 2 produced 21 associations with P ≤ 5x10 -8 (Table 1 and Figure 1). Of these, 18 were previously reported as genome-wide significant and three of them are signals not initially described in Lambert et al: the rare R47H TREM2 coding va...

Background Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of mutant hematopoietic stem cells, confers risk for multiple diseases of aging including hematologic cancer and cardiovascular disease. Whole-exome or genome sequencing can detect CHIP, but due to those assays’ high cost, most population studies have been cross-sectional, sequencing only a single timepoint per individual. Results We developed and validated a cost-effective single molecule molecular inversion probe sequencing (smMIPS) assay for detecting CHIP, targeting the 11 most frequently mutated genes in CHIP along with 4 recurrent mutational hotspots. We sequenced 548 multi-timepoint samples collected from 182 participants in the Women’s Health Initiative cohort, across a median span of 16 years. We detected 178 driver mutations reaching variant allele frequency ≥ 2% in at least one timepoint, many of which were detectable well below this threshold at earlier timepoints. The majority of clonal mutations (52.1%) expanded over time (with a median doubling period of 7.43 years), with the others remaining static or decreasing in size in the absence of any cytotoxic therapy. Conclusions Targeted smMIPS sequencing can sensitively measure clonal dynamics in CHIP. Mutations that reached the conventional threshold for CHIP (2% frequency) tended to continue growing, indicating that after CHIP is acquired, it is generally not lost. The ability to cost-effectively profile CHIP longitudinally will enable future studies to investigate why some CHIP clones expand, and how their dynamics relate to health outcomes at a biobank scale.

Summary Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or ≥50 years of age; females: pre- or post-menopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet<0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet=1.74E-03, I2=89.8), with a significant association in older males (P=1.39E-06) but not younger males (P=0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.

Background: Although the role of radon gas in lung carcinogenesis is well-known, relatively little is known about radon’s role in the pathogenesis or epidemiology of cerebrovascular disease. Methods: We therefore identified postmenopausal women without a history of stroke at the 1993-1998 screening visit of the Women’s Health Initiative Clinical Trials and Observational Study (WHI CT and OS). We linked their geocoded addresses to U.S. Environmental Protection Agency (EPA)-predicted, county-level, indoor, screening radon gas concentrations classified as follows: Zone 3 (<2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (>4 pCi/L). We identified incident strokes based on physician-reviewed, classified, and adjudicated medical records. We measured time from screening to the earliest stroke or censoring date (02/28/20). We used Cox proportional hazards models to estimate radon-related risk of stroke on an attained-age scale as a hazard ratio (HR) and 95% confidence interval (CI), adjusting for WHI design, race/ethnicity, education, homemaker status, U.S. Census region, neighborhood socioeconomic status, smoking, alcohol intake, sodium intake (g/day), 2005 Healthy Eating Index, recreational physical activity (MET-hr/wk), body mass index (kg/m 2 ), systolic blood pressure (mm Hg), as well as history of diabetes, hypercholesterolemia, atrial fibrillation, and deep vein thrombosis/pulmonary embolism. Results: Among 158,906 women (mean, standard deviation [SD] age = 63.1 [7.2] years; 83% white; 9% black; 4% Hispanic; 4% other), we identified 6,979 incident strokes over a mean [SD] follow-up period of 9.3 [5.6] person-years, i.e. 3.41 strokes / 1,000 person-years. The proportion of women with incident stroke was 1.38%, 1.72%, and 1.30% in EPA Radon Zones 3, 2, and 1, respectively. Corresponding incidence rates by EPA Radon Zone were 3.33, 3.43 and 3.49 per 1,000 person-years. Relative to women in Zone 3, those in Zones 2 and 1 had higher adjusted risks of incident stroke: HR (95% CI) = 1.07 (1.00, 1.14) and 1.15 (1.07 , 1.24). Conclusion: Radon gas is a pervasive carcinogen that also may increase susceptibility to a societally burdensome form of cerebrovascular disease, thereby highlighting the potential value of targeted testing, radon-safe construction, and mitigation in stroke prevention.

It has been reported that residents of low socioeconomic status (SES) neighborhoods have a higher risk of developing cardiovascular diseases (CVD). However, most of the previous studies focused on one-time measurement of neighborhood SES in middle-to-older adulthood and lacked demographic diversity to allow for comparisons across different race-and-sex groups. We examined neighborhood SES in childhood, and young, middle, and older adulthood in association with the risk for CVD in Black and White men and women in the Atherosclerosis Risk in Communities Study (1996-2019). We found that lower neighborhood SES in young, middle, and older adulthood, but not in childhood, was associated with a higher risk of CVD later in life. When compared to the highest quartile, the lowest quartile of neighborhood SES in young, middle and older adulthood was associated with 19% (HR (95% confidence interval), 1.19 (1.02, 1.38)), 14% (1.14 (1.00, 1.30)) and 13% (1.13 (0.99, 1.28)) increase in hazard of total CVD, respectively. The association between lower neighborhood SES in older adulthood and higher CVD hazard was particularly strong among Black women. Our study findings support the role of neighborhood SES in cardiovascular health in both Black and White adults.