Assessing the role of the TREM2 p.R47H variant as a risk factor for Alzheimer's disease and frontotemporal dementia

4 páginas, 1 figura, a tabla. Los autores pertenecen a The dementia genetic Spanish consortium (DEGESCO).A non-synonymous genetic rare variant, rs75932628-T (p.R47H), in the TREM2 gene has recently been reported to be a strong genetic risk factor for Alzheimer's disease (AD). Also, rare recessive mutations have been associated with frontotemporal dementia (FTD). We aimed to investigate the role of p.R47H variant in AD and FTD through a multi-center study comprising 3,172 AD and 682 FTD patients and 2,169 healthy controls from Spain. We found that 0.6% of AD cases carried this variant compared to 0.1% of controls (odds ratio [OR]=4.12, 95% confidence interval [CI]: 1.21-14.00, P=0.014). A meta-analysis comprising 32,598 subjects from four previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR=4.11, 95% CI: 2.99-5.68, P=5.27x10-18). We did not find an association between p.R47H and age of onset of AD or family history of dementia. Finally, none of the FTD patients harbored this genetic variant. These data strongly support the important role of p.R47H in AD risk and suggest that this rare genetic variant is not related to FTD.This study was supported by grants from Instituto de Salud Carlos III (PI12/01311 and 12/00013), grants from the Ministry of Science (SAF2010-15558, SAF2009-10434), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain), Consolider (CSD2010-00045), and the Department of Health of the Government of Navarra (refs. 13085 and 3/2008). CR held during the period 2009-2013 a “Torres Quevedo” fellowship from the Spanish Ministry of Science and Technology, co-financed by the European Social Fund. Fundació ACE researchers are indebted to Trinitat Port-Carbó and her family who are supporting Fundació ACE scientific programs.Peer reviewe

The Expanded mtDNA Phylogeny of the Franco-Cantabrian Region Upholds the Pre-Neolithic Genetic Substrate of Basques

The European genetic landscape has been shaped by several human migrations occurred since Paleolithic times. The accumulation of archaeological records and the concordance of different lines of genetic evidence during the last two decades have triggered an interesting debate concerning the role of ancient settlers from the Franco-Cantabrian region in the postglacial resettlement of Europe. Among the Franco-Cantabrian populations, Basques are regarded as one of the oldest and more intriguing human groups of Europe. Recent data on complete mitochondrial DNA genomes focused on macrohaplogroup R0 revealed that Basques harbor some autochthonous lineages, suggesting a genetic continuity since pre-Neolithic times. However, excluding haplogroup H, the most representative lineage of macrohaplogroup R0, the majority of maternal lineages of this area remains virtually unexplored, so that further refinement of the mtDNA phylogeny based on analyses at the highest level of resolution is crucial for a better understanding of the European prehistory. We thus explored the maternal ancestry of 548 autochthonous individuals from various Franco-Cantabrian populations and sequenced 76 mitogenomes of the most representative lineages. Interestingly, we identified three mtDNA haplogroups, U5b1f, J1c5c1 and V22, that proved to be representative of Franco-Cantabria, notably of the Basque population. The seclusion and diversity of these female genetic lineages support a local origin in the Franco-Cantabrian area during the Mesolithic of southwestern Europe, ∼10,000 years before present (YBP), with signals of expansions at ∼3,500 YBP. These findings provide robust evidence of a partial genetic continuity between contemporary autochthonous populations from the Franco-Cantabrian region, specifically the Basques, and Paleolithic/Mesolithic hunter-gatherer groups. Furthermore, our results raise the current proportion (≈15%) of the Franco-Cantabrian maternal gene pool with a putative pre-Neolithic origin to ≈35%, further supporting the notion of a predominant Paleolithic genetic substrate in extant European populations

The COMT Val158 Met polymorphism as an associated risk factor for Alzheimer disease and mild cognitive impairment in APOE 4 carriers

<p>Abstract</p> <p>Background</p> <p>The aim of this study is to examine the influence of the <it>catechol-O-methyltranferase (COMT) </it>gene (polymorphism Val158 Met) as a risk factor for Alzheimer's disease (AD) and mild cognitive impairment of amnesic type (MCI), and its synergistic effect with the <it>apolipoprotein E gene (APOE)</it>.</p> <p>A total of 223 MCI patients, 345 AD and 253 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups.</p> <p>The DNA Bank of the University of the Basque Country (UPV-EHU) (Spain) determined <it>COMT </it>Val158 Met and <it>APOE </it>genotypes using real time polymerase chain reaction (rtPCR) and polymerase chain reaction (PCR), and restriction fragment length polymorphism (RFLPs), respectively. Multinomial logistic regression models were used to determine the risk of AD and MCI.</p> <p>Results</p> <p>Neither <it>COMT </it>alleles nor genotypes were independent risk factors for AD or MCI. The high activity genotypes (GG and AG) showed a synergistic effect with <it>APOE ε4 </it>allele, increasing the risk of AD (OR = 5.96, 95%CI 2.74-12.94, p < 0.001 and OR = 6.71, 95%CI 3.36-13.41, p < 0.001 respectivily). In AD patients this effect was greater in women.</p> <p>In MCI patients such as synergistic effect was only found between AG and <it>APOE ε4 </it>allele (OR = 3.21 95%CI 1.56-6.63, p = 0.02) and was greater in men (OR = 5.88 95%CI 1.69-20.42, p < 0.01).</p> <p>Conclusion</p> <p><it>COMT </it>(Val158 Met) polymorphism is not an independent risk factor for AD or MCI, but shows a synergistic effect with <it>APOE ε4 </it>allele that proves greater in women with AD.</p

Association of the C47T Polymorphism in SOD2 with Amnestic Mild Cognitive Impairment and Alzheimer’s Disease in Carriers of the APOEε4 Allele

Oxidative stress plays an important part in amnestic mild cognitive impairment (aMCI), the prodromal phase of Alzheimer’s disease (AD). Recent evidence shows that polymorphisms in the SOD2 gene affect the elimination of the reactive oxygen species (ROS) generated in mitochondria. The aim of this study was to determine whether the functional rs4880 SNP in the SOD2 gene is a risk factor associated with aMCI and sporadic AD. 216 subjects with aMCI, 355 with AD, and 245 controls have been studied. The SNP rs4880 of the SOD2 gene was genotyped by RT-PCR and the APOE genotype was determined by PCR and RFLPs. Different multinomial logistic regression models were used to determine the risk levels for aMCI and AD. Although the T allele of the SOD2 rs4880 SNP gene (rs4880-T) is not an independent risk for aMCI or AD, this allele increases the risk to aMCI patients carrying at least one APOEε4 allele. Moreover, rs4880-T allele and APOEε4 allele combination has been found to produce an increased risk for AD compared to aMCI reference patients. These results suggest that APOEε4 and rs4880-T genotype may be a risk for aMCI and a predictor of progression from aMCI to AD

Distribution map of haplogroup U5b1f within the Franco-Cantabrian region.

<p>A) Geographic locations of populations surveyed for haplogroup U5b1f (1. Guipuzcoa, 2. South-West Guipuzcoa, 3. Biscay, 4. West Biscay, 5. Alava, 6. South Alava, 7. Northern Navarre, 8. Central-West Navarre, 9. North-East Navarre, 10. North-West Navarre, 11. Lower Navarre, 12. Labourdin, 13. Soule, 14. Bearn, 15. Bigorre, 16. Chalosse, 17. La Rioja, 18. Burgos, 19. Pas Valley, 20. Cantabria, 21. Aragon, 22. Zaragoza, 23. North-East Spain, 24. Madrid and 25. Périgord-Limousin). Frequency values are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067835#pone.0067835.s004" target="_blank">Table S3</a>. B) Grayscale represents spatial variation in haplogroup frequency, with a peak between northeastern Navarre and Iparralde (French Basque Country), and a gradual decreasing trend towards the borders of the distribution. In evolutionary terms, differences in grayscale within the same geographic territory (e.g. Basque area) imply local genetic differentiation.</p

Maximum parsimony trees of haplogroups U5b, J1c and V including the three autochthonous lineages U5b1f, J1c5c1 and V22.

<p>These trees are extracted from the maximum parsimony phylogenetic tree of 76 complete mtDNA sequences of the Franco-Cantabrian region shown in detail in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067835#pone.0067835.s001" target="_blank">Fig. S1</a>. Mutations are displayed along the branches. All mutations are transitions unless a suffix specifies a transversion (A, C, G, T). Recurrent mutations within the complete phylogeny of the Franco-Cantabrian area are underlined. The prefix ‘‘@’’ indicates a back mutation. Mutational hotspot variants such as 16182, 16183, or 16519, or a variation around position 310 or 523–524, as well as length heteroplasmies were not considered for the phylogenetic reconstruction. All the samples are colored according to their geographic origin, as shown in the legend. For phylogeny construction, five previously published mitogenomes belonging to subhaplogroups U5b1f (JX286537 and DQ156208), J1c5c1 (JQ702776 and JQ704051) and V22 (HQ384212) were included (GenBank accession numbers in the tree). German ethnicity was declared for sample JX286537 in GenBank; however, maternal ancestry in southwestern Europe cannot be ruled out owing to the absence of lineage U51bf in populations outside the Franco Cantabrian area (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067835#pone.0067835.s003" target="_blank">Tables S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067835#pone.0067835.s004" target="_blank">S3</a>). French B.C. refers to samples from the French Basque Country.</p

Age estimates for three Franco-Cantabrian autochthonous haplogroups by using rho (r) statistics.

<p>N: number of complete mtDNA sequences used for the age estimates. Calculations were performed based on the mitogenomes from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067835#pone-0067835-g001" target="_blank">Fig. 1</a> rho: average distance to the most recent common ancestor ⁵⁶ sigma: standard error ⁵⁷.</p

MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE epsilon 4 noncarriers: results from the dementia genetics Spanish consortium

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE epsilon4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE epsilon4 AD