Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Descriptive details of lead distributions based on occupation, geophagy practices, and location differences (N = 1056).

Descriptive details of lead distributions based on occupation, geophagy practices, and location differences (N = 1056).</p

De-identified data and detailed information regarding the study participants.

De-identified data and detailed information regarding the study participants.</p

A box plot showing the distribution of lead levels based on location and geophagy practices.

A box plot showing the distribution of lead levels based on location and geophagy practices.</p

Association between geophagy practices among pregnant women and blood lead concentration (N = 1056).

Association between geophagy practices among pregnant women and blood lead concentration (N = 1056).</p

Inclusivity-in-global-research-questionnaire.

Neither artisanal and small-scale gold mining (ASGM) or geophagy practices have received substantial attention related to blood lead levels despite the well documented deleterious effects of lead. This cross-sectional analytical study aimed to document the risk of lead exposure from geophagy and mining-related occupational activities for pregnant women. The study recruited 1056 pregnant women (883 in an ASGM area and 173 in a non-ASGM area) between April 2015 –April 2017. Generalized Linear Model with an identity link function was used to model the association between blood lead levels (BLLs) and geophagy practices and involvement in gold mining. The prevalence of geophagy was 36.2% (95% CI: 33.6, 39.4%) and 6.3% engaged in mining as a primary occupation. Practicing geophagy increased BLLs by 22% (β = 1.22, 95% CI: 1.116, 1.309, p</div

Socio-demographic status among the study participants (N = 1056).

Socio-demographic status among the study participants (N = 1056).</p

STROBE statement—checklist of items that should be included in reports of observational studies.

STROBE statement—checklist of items that should be included in reports of observational studies.</p