This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.
Genome-wide association studies (GWAS) have identified several risk
variants for late-onset Alzheimer's disease (LOAD)1,2. These
common variants have replicable but small effects on LOAD risk and generally do
not have obvious functional effects. Low-frequency coding variants, not detected
by GWAS, are predicted to include functional variants with larger effects on
risk. To identify low frequency coding variants with large effects on LOAD risk,
we performed whole exome-sequencing (WES) in 14 large LOAD families and
follow-up analyses of the candidate variants in several large case-control
datasets. A rare variant in PLD3 (phospholipase-D family,
member 3, rs145999145; V232M) segregated with disease status in two independent
families and doubled risk for AD in seven independent case-control series (V232M
meta-analysis; OR= 2.10, CI=1.47-2.99; p= 2.93×10-5, 11,354
cases and controls of European-descent). Gene-based burden analyses in 4,387
cases and controls of European-descent and 302 African American cases and
controls, with complete sequence data for PLD3, indicate that
several variants in this gene increase risk for AD in both populations (EA: OR=
2.75, CI=2.05-3.68; p=1.44×10-11, AA: OR= 5.48, CI=1.77-16.92;
p=1.40×10-3). PLD3 is highly expressed in
brain regions vulnerable to AD pathology, including hippocampus and cortex, and
is expressed at lower levels in neurons from AD brains compared to control
brains (p=8.10×10-10). Over-expression of PLD3 leads to a
significant decrease in intracellular APP and extracellular Aβ42 and
Aβ40, while knock-down of PLD3 leads to a significant increase in
extracellular Aβ42 and Aβ40. Together, our genetic and functional
data indicate that carriers of PLD3 coding variants have a
two-fold increased risk for LOAD and that PLD3 influences APP
processing. This study provides an example of how densely affected families may
be used to identify rare variants with large effects on risk for disease or
other complex traits.
A genome-wide survival analysis of 14,406 Alzheimer’s disease
(AD) cases and 25,849 controls identified eight previously reported AD risk loci
and fourteen novel loci associated with age at onset. LD score regression of 220
cell types implicated regulation of myeloid gene expression in AD risk. In
particular, the minor allele of rs1057233 (G), within the previously reported
CELF1 AD risk locus, showed association with delayed AD
onset and lower expression of SPI1 in monocytes and
macrophages. SPI1 encodes PU.1, a transcription factor critical
for myeloid cell development and function. AD heritability is enriched within
the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD.
Finally, experimentally altered PU.1 levels affect the expression of mouse
orthologs of many AD risk genes and the phagocytic activity of mouse microglial
cells. Our results suggest that lower SPI1 expression reduces
AD risk by regulating myeloid gene expression and cell function.
An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Genetic association studies have shown the importance of variants in the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit gene cluster on chromosome 15q24-25.1 for the risk of nicotine dependence, smoking, and lung cancer in populations of European descent. We have carried out a detailed study of this region using dense genotyping in both European-Americans and African-Americans. We genotyped 75 known single nucleotide polymorphisms (SNPs) and one sequencing-discovered SNP in an African-American sample (N = 710) and in a European-American sample (N = 2,062). Cases were nicotine-dependent and controls were nondependent smokers. The nonsynonymous CHRNA5 SNP rs16969968 is the most significant SNP associated with nicotine dependence in the full sample of 2,772 subjects [P = 4.49 Â 10 À8
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