- Email: [email protected]
Whole-exome sequencing in dutch families with Alzheimer’s disease
P490
Poster Presentations: P2
Background: The relationship between genetic Alzheimer’s disease (AD) risk and insulin resistance remains uncertain. Methods: The goal of this project was to characterize glucose metabolism in a large cohort of well-characterized individuals (n¼331) with either no dementia (ND) or cognitive impairment due to probable Alzheimer’s disease (AD) and examine the relationship between insulin resistance and genotype. Samples were characterized for fasting glucose, fasting insulin, and apolipoprotein E. All analyses were controlled for age, sex, and education. Results: Subjects with AD exhibited higher fasting insulin (8.1 mU/mL [6.1]), compared to ND subjects (6.9mU/mL [6.2], p¼0.04). ND subjects were more insulin sensitive when assessed using the quantitative insulin sensitivity check index (0.39 [0.07] vs 0.37 [0.06] p¼0.05). We also observed interesting relationships between apolipoprotein E (ApoE) genotype and fasting insulin. ApoE e4 carriers exhibited significantly lower fasting insulin levels than APOE e3/e3 subjects in both diagnosis groups (ND: e3/e3 0.71 [0.4] vs e4 carriers 0.59 [0.4], AD: e3/e3 0.88 [0.4] vs e4 carriers 0.72 [0.4], (p¼0.02)). When subjects were grouped by global clinical dementia rating, APOE e3/e3 subjects with increasing CDR global score exhibited a stepwise increase in fasting insulin levels, while APOE e4 carriers exhibited a stepwise increase only to the level of CDR ¼1, before fasting insulin levels drastically dropped in the most severely affected subjects. Conclusions: These analyses suggest a relationship between ApoE genotype and compensatory increases in insulin levels with AD diagnosis and progression.
P2-023
VITAMIN D RECEPTOR POLYMORPHISMS AND ALZHEIMER DISEASE
Ging-Yuek Robin Hsiung1, Alice Fok1, Jacqueline A. Pettersen2, University of British Columbia, Vancouver, BC, Canada; 2University of British Columbia-Northern Medical Program, Prince George, BC, Canada. Contact e-mail: [email protected] 1
Background: Recent studies have suggested an association between
low Vitamin D level and cognitive impairment. Some of the observed differences may be attributable to the affinity of vitamin D receptor for the Vitamin D3 ligand. We hypothesize that genetic polymorphisms in the Vitamin D receptor may influence our body response to Vitamin D, and may incur risk of AD. In the current study, we compared genotype frequencies in a cohort of AD patients with controls in a Canadian population. Methods: We examined 8 SNPs in the Vitamin D receptor, including Fok1, Taq1, Apa1, Bsm1, Cdx, Tru91, rs7968585, and rs7976091. There are 248 patients clinically diagnosed with probable AD enrolled through a dementia specialty clinic, and 78 subjects who are cognitively intact enrolled in a study to screen for Vitamin D deficiency. All subjects are Canadians of European descent. Genotyping was done by TaqMan assay (ABI3700). Association was tested by Chi Square followed by logistic regression to adjust for the effect of APOE, sex, age, and multiple comparisons. We also examined the correlation between these polymorphisms to total Vitamin D3 levels in our cohort. Results: There are significant differences between the age of AD patients (mean 70.5) compared to the controls (57.0, p<0.001). In the initial screening phase, we found association between Taq1 (P¼0.04) and Apa1 (P¼0.015) with AD, but not with the other SNPs. After adjusting for effect of age, sex, and APOE genotype (e4 carriers vs non carriers), the effect of Taq1 disappears, but the effect of Apa1 remains, suggesting that the CC genotype is associated with an increased risk of AD. Inter-
estingly, there is no significant association between this polymorphism and serum Vitamin D3 level. Conclusions: Our findings suggest that the Vitamin D receptor polymorphism Apa1 is associated with increased risk of AD. However, there is no association between this polymorphism to total serum Vitamin D3 levels. Further analyses in a larger scale study is warranted to elucidate the role of Vitamin D and its receptor polymorphisms as a risk for AD.
P2-024
WHOLE-EXOME SEQUENCING IN DUTCH FAMILIES WITH ALZHEIMER’S DISEASE
Tsz Hang Wong1, Sven J. van der Lee1, Lieke H.H. Meeter1, Jeroen G.J. van Rooij1, M. Arfan Ikram1, Rick van Minkelen1, Andre G. Uitterlinden1,2, Najaf Amin1, Cornelia M. van Duijn1, John C. van Swieten1,3, 1Erasmus Medical Center, Rotterdam, Netherlands; 2 Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, Netherlands; 3Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands. Contact e-mail: t.h.wong@ erasmusmc.nl Background: Alzheimer’s disease (AD) is the most common sub-
type of dementia, and is characterized by progressive cognitive dysfunction. It is a complex disorder that has a strong genetic component. Although several causative mutations and genetic risk factors are known for AD, mutations in some familial cases are still unknown. Development in next generation sequencing technologies has enabled us to identify additional genetic variations explaining this complex disorder. Methods: In this study, we sequenced eight Dutch families with a high burden of AD, not explained by PSEN1, PSEN2 and APP mutations, using whole exome sequencing (WES). In each family, we sequenced at least two affected individuals and one unaffected family member (if available). Results: Screening of known mutations in SORL1, TREM2 and PLD3 revealed a PLD3 A442A variant in one family, but this variant did not segregate with disease. We focused on nonsynonymous, splice site, stop, frameshift insertion and frameshift deletion variants that were shared by cases but absent in the unaffected family member. Variants with a frequency higher than 0.5% in 1000 Genomes, Exome Variants Server, Exome Aggregation Corsortium, Genome of the Netherlands and the non-AD controls in the Rotterdam Study (n¼2173) were filtered out. This resulted in 12 to 84 variants per family. Filtered variants in the same gene in two or more families were assumed as candidates. In 6 of 8 families candidate variants in PRSS3 were found. Of those, four families also shared the same variants. Besides, variants in CD163L1, which was found in earlier studies, were found in three families with late onset AD. Conclusions: The candidate variants will be tested for segregation in all affected members. Additionally we will exome sequence extra affected and/or unaffected to reduce the number of candidate variants.
P2-025
GENETIC AND EPIGENETIC INFLUENCES ON BRAIN GENE EXPRESSION IN PSP
Mariet Allen1, Xue Wang1, Curtis S. Younkin1, Jeremy D. Burgess1, Travis Ballard1, Daniel Serie1, Chen Wang2, Zhifu Sun2, Saurabh Baheti2, Minerva M. Carrasquillo1, Thuy Nguyen1, Kimberly G. Malphrus1, Sarah Lincoln1, Fanggeng Zou1, High-Seng Chai2, Gerard D. Schellenberg3, Steven G. Younkin1, Julia Crook1, Tamas Ordog4, Yan W. Asmann1, Dennis W. Dickson1, Nilufer Taner1, 1Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN, USA; 3University of Pennsylvania, Philadelphia, PA, USA; 4Mayo Clinic Center for
Poster Presentations: P2
Background: The relationship between genetic Alzheimer’s disease (AD) risk and insulin resistance remains uncertain. Methods: The goal of this project was to characterize glucose metabolism in a large cohort of well-characterized individuals (n¼331) with either no dementia (ND) or cognitive impairment due to probable Alzheimer’s disease (AD) and examine the relationship between insulin resistance and genotype. Samples were characterized for fasting glucose, fasting insulin, and apolipoprotein E. All analyses were controlled for age, sex, and education. Results: Subjects with AD exhibited higher fasting insulin (8.1 mU/mL [6.1]), compared to ND subjects (6.9mU/mL [6.2], p¼0.04). ND subjects were more insulin sensitive when assessed using the quantitative insulin sensitivity check index (0.39 [0.07] vs 0.37 [0.06] p¼0.05). We also observed interesting relationships between apolipoprotein E (ApoE) genotype and fasting insulin. ApoE e4 carriers exhibited significantly lower fasting insulin levels than APOE e3/e3 subjects in both diagnosis groups (ND: e3/e3 0.71 [0.4] vs e4 carriers 0.59 [0.4], AD: e3/e3 0.88 [0.4] vs e4 carriers 0.72 [0.4], (p¼0.02)). When subjects were grouped by global clinical dementia rating, APOE e3/e3 subjects with increasing CDR global score exhibited a stepwise increase in fasting insulin levels, while APOE e4 carriers exhibited a stepwise increase only to the level of CDR ¼1, before fasting insulin levels drastically dropped in the most severely affected subjects. Conclusions: These analyses suggest a relationship between ApoE genotype and compensatory increases in insulin levels with AD diagnosis and progression.
P2-023
VITAMIN D RECEPTOR POLYMORPHISMS AND ALZHEIMER DISEASE
Ging-Yuek Robin Hsiung1, Alice Fok1, Jacqueline A. Pettersen2, University of British Columbia, Vancouver, BC, Canada; 2University of British Columbia-Northern Medical Program, Prince George, BC, Canada. Contact e-mail: [email protected] 1
Background: Recent studies have suggested an association between
low Vitamin D level and cognitive impairment. Some of the observed differences may be attributable to the affinity of vitamin D receptor for the Vitamin D3 ligand. We hypothesize that genetic polymorphisms in the Vitamin D receptor may influence our body response to Vitamin D, and may incur risk of AD. In the current study, we compared genotype frequencies in a cohort of AD patients with controls in a Canadian population. Methods: We examined 8 SNPs in the Vitamin D receptor, including Fok1, Taq1, Apa1, Bsm1, Cdx, Tru91, rs7968585, and rs7976091. There are 248 patients clinically diagnosed with probable AD enrolled through a dementia specialty clinic, and 78 subjects who are cognitively intact enrolled in a study to screen for Vitamin D deficiency. All subjects are Canadians of European descent. Genotyping was done by TaqMan assay (ABI3700). Association was tested by Chi Square followed by logistic regression to adjust for the effect of APOE, sex, age, and multiple comparisons. We also examined the correlation between these polymorphisms to total Vitamin D3 levels in our cohort. Results: There are significant differences between the age of AD patients (mean 70.5) compared to the controls (57.0, p<0.001). In the initial screening phase, we found association between Taq1 (P¼0.04) and Apa1 (P¼0.015) with AD, but not with the other SNPs. After adjusting for effect of age, sex, and APOE genotype (e4 carriers vs non carriers), the effect of Taq1 disappears, but the effect of Apa1 remains, suggesting that the CC genotype is associated with an increased risk of AD. Inter-
estingly, there is no significant association between this polymorphism and serum Vitamin D3 level. Conclusions: Our findings suggest that the Vitamin D receptor polymorphism Apa1 is associated with increased risk of AD. However, there is no association between this polymorphism to total serum Vitamin D3 levels. Further analyses in a larger scale study is warranted to elucidate the role of Vitamin D and its receptor polymorphisms as a risk for AD.
P2-024
WHOLE-EXOME SEQUENCING IN DUTCH FAMILIES WITH ALZHEIMER’S DISEASE
Tsz Hang Wong1, Sven J. van der Lee1, Lieke H.H. Meeter1, Jeroen G.J. van Rooij1, M. Arfan Ikram1, Rick van Minkelen1, Andre G. Uitterlinden1,2, Najaf Amin1, Cornelia M. van Duijn1, John C. van Swieten1,3, 1Erasmus Medical Center, Rotterdam, Netherlands; 2 Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden, Netherlands; 3Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam, Netherlands. Contact e-mail: t.h.wong@ erasmusmc.nl Background: Alzheimer’s disease (AD) is the most common sub-
type of dementia, and is characterized by progressive cognitive dysfunction. It is a complex disorder that has a strong genetic component. Although several causative mutations and genetic risk factors are known for AD, mutations in some familial cases are still unknown. Development in next generation sequencing technologies has enabled us to identify additional genetic variations explaining this complex disorder. Methods: In this study, we sequenced eight Dutch families with a high burden of AD, not explained by PSEN1, PSEN2 and APP mutations, using whole exome sequencing (WES). In each family, we sequenced at least two affected individuals and one unaffected family member (if available). Results: Screening of known mutations in SORL1, TREM2 and PLD3 revealed a PLD3 A442A variant in one family, but this variant did not segregate with disease. We focused on nonsynonymous, splice site, stop, frameshift insertion and frameshift deletion variants that were shared by cases but absent in the unaffected family member. Variants with a frequency higher than 0.5% in 1000 Genomes, Exome Variants Server, Exome Aggregation Corsortium, Genome of the Netherlands and the non-AD controls in the Rotterdam Study (n¼2173) were filtered out. This resulted in 12 to 84 variants per family. Filtered variants in the same gene in two or more families were assumed as candidates. In 6 of 8 families candidate variants in PRSS3 were found. Of those, four families also shared the same variants. Besides, variants in CD163L1, which was found in earlier studies, were found in three families with late onset AD. Conclusions: The candidate variants will be tested for segregation in all affected members. Additionally we will exome sequence extra affected and/or unaffected to reduce the number of candidate variants.
P2-025
GENETIC AND EPIGENETIC INFLUENCES ON BRAIN GENE EXPRESSION IN PSP
Mariet Allen1, Xue Wang1, Curtis S. Younkin1, Jeremy D. Burgess1, Travis Ballard1, Daniel Serie1, Chen Wang2, Zhifu Sun2, Saurabh Baheti2, Minerva M. Carrasquillo1, Thuy Nguyen1, Kimberly G. Malphrus1, Sarah Lincoln1, Fanggeng Zou1, High-Seng Chai2, Gerard D. Schellenberg3, Steven G. Younkin1, Julia Crook1, Tamas Ordog4, Yan W. Asmann1, Dennis W. Dickson1, Nilufer Taner1, 1Mayo Clinic, Jacksonville, FL, USA; 2Mayo Clinic, Rochester, MN, USA; 3University of Pennsylvania, Philadelphia, PA, USA; 4Mayo Clinic Center for