Sigrid Botne Sando

Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease.

We conducted a search for rare, functional variants altering susceptibility to Alzheimers disease that exploited knowledge of common variants associated with the same disease. We found that loss-of-function variants in ABCA7 confer risk of Alzheimers disease in Icelanders (odds ratio (OR) = 2.12, P = 2.2 × 10−13) and discovered that the association replicated in study groups from Europe and the United States (combined OR = 2.03, P = 6.8 × 10−15).

APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

BackgroundThe objective of this study was to analyze factors influencing the risk and timing of Alzheimers disease (AD) in central Norway. The APOE ε4 allele is the only consistently identified risk factor for late onset Alzheimers disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (APOE) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the APOE ε4 allele on the risk and the age at onset of AD in this population.Methods376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the APOE alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.ResultsOdds Ratio (OR) for developing AD was significantly increased in carriers of the APOE ε4 allele compared to individuals with the APOE ε3/ε3 genotype. Individuals carrying APOE ε4/ε4 had OR of 12.9 for developing AD, while carriers of APOE ε2/ε4 and APOE ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the APOE ε4 allele was weaker with increasing age. Carrying the APOE ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the APOE ε4 allele, to 75.3 in carriers of one APOE ε4 allele and 72.9 in carriers of two APOE ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by APOE ε4 alleles.ConclusionAPOE ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.

Evidence for an association between KIBRA and late-onset Alzheimer's disease

We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimers disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and three of its four known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (P<0.010, corrected) in a study of laser-capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (P=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (P=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.

Genetic variation of Omi/HtrA2 and Parkinson's disease

Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinsons disease. This sequencing study of Omi/HtrA2 in 95 probands with apparent autosomal dominant inheritance of Parkinsons disease did not identify any pathogenic mutations. In addition, there was no association between common variations in the Omi/HtrA2 gene and susceptibility to Parkinsons disease in any of our four patient-control series (n=2373). Taken together our results do not support a role for Omi/HtrA2 variants in the pathogenesis of Parkinsons disease.

Replication of BIN1 association with Alzheimer's disease and evaluation of genetic interactions

The most recent late-onset Alzheimers disease (LOAD) genome-wide association study revealed genome-wide significant association of two new loci: rs744373 near BIN1 (p = 1.6 × 10-11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (p = 6.5 × 10-9). We have genotyped these variants in a large (3,287 LOAD, 4,396 controls), independent dataset comprising eleven case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and also tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 status. Meta-analysis results showed no evidence of series heterogeneity and logistic regression analysis successfully replicated the association of BIN1 (rs744373) with LOAD with an odds ratio (OR = 1.17, p = 1.1 × 10-4) comparable to that previously reported (OR = 1.15). The variant near EXOC3L2 (rs597668) showed only suggestive association with LOAD (p = 0.09) after correcting for the presence of the APOE ε4 allele. Addition of our follow-up data to the results previously reported increased the strength of evidence for association with BIN1 (11,825 LOAD, 32,570 controls, rs744373 Fisher combined p = 3.8 × 10-20). We also tested for epistatic interaction between these variants and APOE ε4 as well as with the previously replicated LOAD GWAS genes (CLU: rs11136000, CR1: rs3818361, and PICALM: rs3851179). No significant interactions between these genes were detected. In summary, we provide additional evidence for the variant near BIN1 (rs744373) as a LOAD risk modifier, but our results indicate that the effect of EXOC3L2 independent of APOE ε4 should be studied further.

Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease

Background— Epidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and Results— Using summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05–1.11; P=2.86×10−8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04–1.11; P=3.38×10−8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. Conclusions— We demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.

Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study

BackgroundA recently published genome-wide association study (GWAS) of late-onset Alzheimers disease (LOAD) revealed genome-wide significant association of variants in or near MS4A4A, CD2AP, EPHA1 and CD33. Meta-analyses of this and a previously published GWAS revealed significant association at ABCA7 and MS4A, independent evidence for association of CD2AP, CD33 and EPHA1 and an opposing yet significant association of a variant near ARID5B. In this study, we genotyped five variants (in or near CD2AP, EPHA1, ARID5B, and CD33) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and APOE ε4 dosage.ResultsWe found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for EPHA1 (rs11767557; OR = 0.87, p = 5 × 10-4) and CD33 (rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two ARID5B variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the CD2AP variant (rs9349407, p = 0.56).ConclusionsOur data overwhelmingly support the association of EPHA1 and CD33 variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10-15 (EPHA1) and 1.8 × 10-13 (CD33).

Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at- diagnosis and brain gene expression: an association study with mechanistic implications

BackgroundGlutathione S-transferase omega-1 and 2 genes (GSTO1, GSTO2), residing within an Alzheimer and Parkinson disease (AD and PD) linkage region, have diverse functions including mitigation of oxidative stress and may underlie the pathophysiology of both diseases. GSTO polymorphisms were previously reported to associate with risk and age-at-onset of these diseases, although inconsistent follow-up study designs make interpretation of results difficult. We assessed two previously reported SNPs, GSTO1 rs4925 and GSTO2 rs156697, in AD (3,493 ADs vs. 4,617 controls) and PD (678 PDs vs. 712 controls) for association with disease risk (case-controls), age-at-diagnosis (cases) and brain gene expression levels (autopsied subjects).ResultsWe found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).ConclusionThese results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.

LRRK2 mutations are not common in Alzheimer's disease

The development of common age-related neurodegenerative disorders as Parkinsons disease and Alzheimers disease (AD) are influenced by genetic factors. Recently, pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified in familial Parkinsonism. Individuals in some of these families developed symptoms of dementia with Lewy-bodies and AD. The LRRK2 gene is also located within a locus on chromosome 12 reported in late-onset AD, and is therefore a good candidate gene for dementia. A series of 242 patients from Norway diagnosed clinically with dementia were included in the study, the majority were diagnosed with AD. Individuals were screened for the presence of seven known pathogenic mutations previously reported in the LRRK2 gene. We did not identify LRRK2 mutations in our series of dementia patients, indicating that known pathogenic mutations are not common in patients clinically diagnosed with AD. However, these results do not exclude a possible role of other genetic variants within the LRRK2 gene in AD or other forms of dementia.

Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort

Background Results conflict concerning the relevance of APOE alleles on the development of dementia with Lewy bodies (DLB), though they are well established in connection with Alzheimers disease (AD). The role of APOE alleles in a Norwegian cohort of patients with DLB was therefore examined compared with patients with AD and healthy control individuals. Methods The study included 156 patients with DLB diagnosed according to the consensus criteria guidelines, 519 patients diagnosed with AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimers Disease and Related Disorders Association (NINCDS/ARDRA) criteria and 643 healthy elderly volunteers. Patients were recruited through hospitals, outpatient clinics, nursing homes or from local care authorities in central and south-western parts of Norway. Healthy individuals were recruited from caregivers and societies for retired people. Results Subjects carrying an APOE ε2 allele had a reduced risk for developing DLB (OR 0.4, CI 0.3 to 0.8, p=0.004), and the onset of disease was delayed by 4 years (p=0.01, Mann–Whitney U test). Conversely, the APOE ε4 allele increased the risk for development of DLB (OR 5.9, CI 2.7 to 13.0, p<0.0005 for homozygotes). Similar results were found for patients with AD regarding the effect of APOE ε2, though the protective effect appeared to be slightly less pronounced than in DLB. This study is one of the largest regarding DLB and APOE to date. Conclusion The results indicate that APOE ε2, a protective factor in AD, has a clear beneficial effect on the development of DLB also.