- Email: [email protected]
THE HERITABILITY OF AMYLOID DEPOSITION IN THE BRAINS OF OLDER PEOPLE: THE OLDER AUSTRALIAN TWINS STUDY
Poster Presentations: Sunday, July 16, 2017 P1-162
P305
GENETIC ANALYSES OF YOUNG PATIENTS WITH ALZHEIMER’S DISEASE FROM NEXT GENERATION SEQUENCING
Vo Van Giau1, Eva Bagyinszky2, Kyu Hwan Shim3, Youngsoon Yang4, Young Chul Youn5, Seong Soo An3, Sang Yun Kim6, 1Department of Bionano Technology, Gachon University, Sungnam, Republic of South Korea; 2Gachon University, Seongnam, Republic of South Korea; 3Department of Bionano Technology, Gachon University, Seongnam, Republic of South Korea; 4Department of Neurology, Veterans Hospital, Seoul, Republic of South Korea; 5Chung-Ang University Hospital, Seoul, Republic of South Korea; 6Seoul National University Bundang Hospital, Sungnam, Republic of South Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common form
of dementia. Many mutations in Amyloid precursor protein (APP), Presenilin 1 and 2 (PSEN 1 and PSEN 2) demonstrated to be the pathogenic causes of early-onset AD (EOAD) with less than 5 % of all AD cases. Apolipoprotein E (34) allele became a significant genetic risk factor for both EOAD and late-onset AD (LOAD). Genome-wide association studies (GWAS) and the next-generation sequencing (NGS) studies suggested additional genetic risk factor 21 loci for AD. From increased number of risk genes for AD, simultaneous screening of multiple genes would be more efficient to understand and correlate with the genetic etiology than gene-by-gene testing. Methods: Previously, 50 genes were suggested as gene panel for AD genetic study. Here, NGS panel study was performed on 92 Korean clinically confirmed EOAD cases. Results: Remarkably, 6.5% of EOAD cases carries a pathogenic mutations or risk variants in APP, PSEN1 and PSEN2, confirming the direct patho-mechanisms in neurodegenerative disease. In APP, one novel mutation (V225A) was found, potentially pathogenic. Four novel missense mutations were found in PSEN1 (T119I; G209A; L232P and G417A), and one patient carried PSEN2 (H169N) mutation. The In silico characterization of APP p.V225A, PSEN1 p.T119I; PSEN1 p.G209A; PSEN1 p.L232P, PSEN1 p.G417A and PSEN2 H169N variants strongly suggested all of them as pathogenic. Furthermore, at least 40 novel mutations were discovered from a total of 143 missense mutations among 37 genes out of 50 genes in the panel. Above mutations could be strong risk genes for AD patients. The correlations between genes and patients’ phenotypes could be complicated. Further studies are needed to verify whether these genetic variations could contribute to the clinical and/or neuropathological phenotypes, or have disease modifying effects. Conclusions: Our results suggested that multigene panel testing would be an effective approach for mutation screening in AD-related genes rather than classic Sanger sequencing testing. We also demonstrated that NGS panel of 50 genes would be a
Figure 1. The location of candidate gene on chromosomes.
powerful tool for rapid analysis of known disease genes in large patient cohorts.
P1-163
THE HERITABILITY OF AMYLOID DEPOSITION IN THE BRAINS OF OLDER PEOPLE: THE OLDER AUSTRALIAN TWINS STUDY
Perminder S. Sachdev1,2, Christopher C. Rowe3,4, Anbupalam Thalamuthu2, Melissa J. Slavin5, Wei Wen1,2 and OATS Collaborative Team, 1Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, Australia; 2Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; 3The University of Melbourne, Parkville, Australia; 4Austin Health, Heidelberg, Australia; 5Dementia Collaborative Research Centre – Assessment and Better Care (DCRC-ABC), School of Psychiatry, University of New South Wales, Sydney, Australia. Contact e-mail: [email protected] Background: Both genetic and environmental factors are important in determining the deposition of brain amyloid, but their relative contributions are not known. The classical twin design is an excellent method to determine this, since monozygotic twins (MZ) share 100% of the genome while dizygotic twins (DZ), like siblings, share only 50%. Methods: 60 participants (18 MZ, 12 DZ pairs) from the Older Australian Twins Study (OATS) had PET scans with C11-PiB (10 mCi bolus i.v. injection over 30 s and 20 min acquisition) at the Austin Hospital, Melbourne. They also had an MRI scan and a detailed neuropsychological and clinical evaluation. Activity in regions of interest (ROIs) was corrected for body weight and dose to produce Standard Uptake Value (SUV) data, and SUV Ratio (SUVR) was calculated: SUVR ¼ SUVROI/SUVCEREBELLUM. Heritability (h2) was measured using the Open Mx package in the best fit (AE) model. Results: The mean (SD) age of the sample was 74.5 (5.9) for MZ and 74.5 (4.7) for DZ twins, with more women in the DZ group (20/24 vs. 18/36, p<.01). The MMSE scores of the MZ and DZ twins were 28.2 (1.5) and 29.2 (1.3) respectively (p<.05). Two participants in each group received a diagnosis of mild cognitive impairment (MCI). There were no significant differences in the salient vascular risk factors between the groups; 14 participants were APOE ε4 +ve. The intra-class correlations between MZ and DZ twins for the global SUVR were 0.29 and 0.14 respectively; heritability h2of
P306
Poster Presentations: Sunday, July 16, 2017
Table The heritability of amyloid burden in the brains of older individuals (MZ monozygotic twins; DZ dizygotic twins; ICC intra-class correlation coefficients; h2 heritability; E environmental influence; AE additive genetics-environmental model). SUVR Standard Uptake Value Ratio. The effects of age and sex are in the AE model
Brain Region
h2
E
MZ (N¼36) ICC
DZ (n¼24) ICC
Age p
Sex p
GLOBAL SUVR Ventrolateral Prefrontal Orbitofrontal Anterior Cingulate Gyrus Posterior Cingulate Gyrus/ Precuneus Parietal Lobe Occipital Lobe Temporal Lobe Mesial Temporal Striatum
0.29 0.37
0.71 0.63
0.29 0.37
0.14 0.19
<0.005 <0.005
0.38 0.58
0.44 0.01
0.56 0.99
0.44 0.01
0.22 0.01
<0.005 0.01
0.51 0.84
0.00
1.00
0.00
0.00
<0.005
0.06
0.37 0.28 0.00 0.38 0.12
0.63 0.72 1.00 0.62 0.88
0.37 0.28 0.00 0.37 0.12
0.18 0.14 0.00 0.20 0.06
<0.005 <0.005 <0.005 0.01 <0.005
0.24 0.14 0.39 0.03 0.01
global SUVR was moderate (0.29), and that for ROIs ranged from 0.0 to 0.44, after correcting for age and sex (Table). The correlations between SUVR in different brains were high (0.58 to 0.86). Using 1.5 SUVR as the cut-off, 6/60 (10%) (2 MZ and 4 DZ) were positive; all were discordant with their co-twins. SUVR increased with age, and was significantly correlated with global cognition, memory and attention/processing speed, but not with vascular risk factors. Conclusions: Amyloid load in the brains of cognitively normal older people has moderate heritability with suggestion of strong environmental influences. A larger study (currently ongoing) will help interrogate some of these factors. P1-164
AGE MODERATES EFFECTS OF PICALM RS541458 ON COGNITIVE IMPAIRMENT AND BRAIN STRUCTURE AND FUNCTIONS
Zhen Liu, Zhanjun Zhang, State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China. Contact e-mail: [email protected] Background: The PICALMrs541458 T allele has been recognized as
a risk factor for late-onset Alzheimer’s disease. And age might modulate the effects of genetic factors on cognitive functions and brain. Thus, the current study intended to examine whether the effects of rs541458 polymorphism on cognitive functions, resting state functional connectivity and gray matter volume would be modulated by age in Chinese non-demented elderly. Methods: We enrolled 657 non-demented old subjects to evaluate their cognitions through a series of neuropsychological tests and to detect rs541458 and APOE genotype through their blood samples using Taqman allele-specific assays. Among them, 78 participants received T1weighted structural imaging and resting state functional magnetic resonance imaging. Results: The results from neuropsychological tests showed that interactive effects of rs5414583age exhibited on executive function and processing speed after controlling for gender, years of education and APOEε4 status. The effects of
rs541458 on resting state functional connectivity of the left superior parietal gyrus within left frontal-parietal network and gray matter volume of left middle temporal gyrus were modulated by age as well. Furthermore, the reduction of functional connectivity of superior parietal gyrus was closely related with better executive function in the T allele carriers-<65 years old group. And the increased volume of left middle temporal gyrus was significantly related with better executive function in the two CC genotype groups. Conclusions: Our results uncover the modulation of age on the PICALM rs541458’ effects on cognitive impairments and brain functional and structural measurements and may be beneficial for further genetic association studies.
P305
GENETIC ANALYSES OF YOUNG PATIENTS WITH ALZHEIMER’S DISEASE FROM NEXT GENERATION SEQUENCING
Vo Van Giau1, Eva Bagyinszky2, Kyu Hwan Shim3, Youngsoon Yang4, Young Chul Youn5, Seong Soo An3, Sang Yun Kim6, 1Department of Bionano Technology, Gachon University, Sungnam, Republic of South Korea; 2Gachon University, Seongnam, Republic of South Korea; 3Department of Bionano Technology, Gachon University, Seongnam, Republic of South Korea; 4Department of Neurology, Veterans Hospital, Seoul, Republic of South Korea; 5Chung-Ang University Hospital, Seoul, Republic of South Korea; 6Seoul National University Bundang Hospital, Sungnam, Republic of South Korea. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is the most common form
of dementia. Many mutations in Amyloid precursor protein (APP), Presenilin 1 and 2 (PSEN 1 and PSEN 2) demonstrated to be the pathogenic causes of early-onset AD (EOAD) with less than 5 % of all AD cases. Apolipoprotein E (34) allele became a significant genetic risk factor for both EOAD and late-onset AD (LOAD). Genome-wide association studies (GWAS) and the next-generation sequencing (NGS) studies suggested additional genetic risk factor 21 loci for AD. From increased number of risk genes for AD, simultaneous screening of multiple genes would be more efficient to understand and correlate with the genetic etiology than gene-by-gene testing. Methods: Previously, 50 genes were suggested as gene panel for AD genetic study. Here, NGS panel study was performed on 92 Korean clinically confirmed EOAD cases. Results: Remarkably, 6.5% of EOAD cases carries a pathogenic mutations or risk variants in APP, PSEN1 and PSEN2, confirming the direct patho-mechanisms in neurodegenerative disease. In APP, one novel mutation (V225A) was found, potentially pathogenic. Four novel missense mutations were found in PSEN1 (T119I; G209A; L232P and G417A), and one patient carried PSEN2 (H169N) mutation. The In silico characterization of APP p.V225A, PSEN1 p.T119I; PSEN1 p.G209A; PSEN1 p.L232P, PSEN1 p.G417A and PSEN2 H169N variants strongly suggested all of them as pathogenic. Furthermore, at least 40 novel mutations were discovered from a total of 143 missense mutations among 37 genes out of 50 genes in the panel. Above mutations could be strong risk genes for AD patients. The correlations between genes and patients’ phenotypes could be complicated. Further studies are needed to verify whether these genetic variations could contribute to the clinical and/or neuropathological phenotypes, or have disease modifying effects. Conclusions: Our results suggested that multigene panel testing would be an effective approach for mutation screening in AD-related genes rather than classic Sanger sequencing testing. We also demonstrated that NGS panel of 50 genes would be a
Figure 1. The location of candidate gene on chromosomes.
powerful tool for rapid analysis of known disease genes in large patient cohorts.
P1-163
THE HERITABILITY OF AMYLOID DEPOSITION IN THE BRAINS OF OLDER PEOPLE: THE OLDER AUSTRALIAN TWINS STUDY
Perminder S. Sachdev1,2, Christopher C. Rowe3,4, Anbupalam Thalamuthu2, Melissa J. Slavin5, Wei Wen1,2 and OATS Collaborative Team, 1Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, Australia; 2Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia; 3The University of Melbourne, Parkville, Australia; 4Austin Health, Heidelberg, Australia; 5Dementia Collaborative Research Centre – Assessment and Better Care (DCRC-ABC), School of Psychiatry, University of New South Wales, Sydney, Australia. Contact e-mail: [email protected] Background: Both genetic and environmental factors are important in determining the deposition of brain amyloid, but their relative contributions are not known. The classical twin design is an excellent method to determine this, since monozygotic twins (MZ) share 100% of the genome while dizygotic twins (DZ), like siblings, share only 50%. Methods: 60 participants (18 MZ, 12 DZ pairs) from the Older Australian Twins Study (OATS) had PET scans with C11-PiB (10 mCi bolus i.v. injection over 30 s and 20 min acquisition) at the Austin Hospital, Melbourne. They also had an MRI scan and a detailed neuropsychological and clinical evaluation. Activity in regions of interest (ROIs) was corrected for body weight and dose to produce Standard Uptake Value (SUV) data, and SUV Ratio (SUVR) was calculated: SUVR ¼ SUVROI/SUVCEREBELLUM. Heritability (h2) was measured using the Open Mx package in the best fit (AE) model. Results: The mean (SD) age of the sample was 74.5 (5.9) for MZ and 74.5 (4.7) for DZ twins, with more women in the DZ group (20/24 vs. 18/36, p<.01). The MMSE scores of the MZ and DZ twins were 28.2 (1.5) and 29.2 (1.3) respectively (p<.05). Two participants in each group received a diagnosis of mild cognitive impairment (MCI). There were no significant differences in the salient vascular risk factors between the groups; 14 participants were APOE ε4 +ve. The intra-class correlations between MZ and DZ twins for the global SUVR were 0.29 and 0.14 respectively; heritability h2of
P306
Poster Presentations: Sunday, July 16, 2017
Table The heritability of amyloid burden in the brains of older individuals (MZ monozygotic twins; DZ dizygotic twins; ICC intra-class correlation coefficients; h2 heritability; E environmental influence; AE additive genetics-environmental model). SUVR Standard Uptake Value Ratio. The effects of age and sex are in the AE model
Brain Region
h2
E
MZ (N¼36) ICC
DZ (n¼24) ICC
Age p
Sex p
GLOBAL SUVR Ventrolateral Prefrontal Orbitofrontal Anterior Cingulate Gyrus Posterior Cingulate Gyrus/ Precuneus Parietal Lobe Occipital Lobe Temporal Lobe Mesial Temporal Striatum
0.29 0.37
0.71 0.63
0.29 0.37
0.14 0.19
<0.005 <0.005
0.38 0.58
0.44 0.01
0.56 0.99
0.44 0.01
0.22 0.01
<0.005 0.01
0.51 0.84
0.00
1.00
0.00
0.00
<0.005
0.06
0.37 0.28 0.00 0.38 0.12
0.63 0.72 1.00 0.62 0.88
0.37 0.28 0.00 0.37 0.12
0.18 0.14 0.00 0.20 0.06
<0.005 <0.005 <0.005 0.01 <0.005
0.24 0.14 0.39 0.03 0.01
global SUVR was moderate (0.29), and that for ROIs ranged from 0.0 to 0.44, after correcting for age and sex (Table). The correlations between SUVR in different brains were high (0.58 to 0.86). Using 1.5 SUVR as the cut-off, 6/60 (10%) (2 MZ and 4 DZ) were positive; all were discordant with their co-twins. SUVR increased with age, and was significantly correlated with global cognition, memory and attention/processing speed, but not with vascular risk factors. Conclusions: Amyloid load in the brains of cognitively normal older people has moderate heritability with suggestion of strong environmental influences. A larger study (currently ongoing) will help interrogate some of these factors. P1-164
AGE MODERATES EFFECTS OF PICALM RS541458 ON COGNITIVE IMPAIRMENT AND BRAIN STRUCTURE AND FUNCTIONS
Zhen Liu, Zhanjun Zhang, State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China. Contact e-mail: [email protected] Background: The PICALMrs541458 T allele has been recognized as
a risk factor for late-onset Alzheimer’s disease. And age might modulate the effects of genetic factors on cognitive functions and brain. Thus, the current study intended to examine whether the effects of rs541458 polymorphism on cognitive functions, resting state functional connectivity and gray matter volume would be modulated by age in Chinese non-demented elderly. Methods: We enrolled 657 non-demented old subjects to evaluate their cognitions through a series of neuropsychological tests and to detect rs541458 and APOE genotype through their blood samples using Taqman allele-specific assays. Among them, 78 participants received T1weighted structural imaging and resting state functional magnetic resonance imaging. Results: The results from neuropsychological tests showed that interactive effects of rs5414583age exhibited on executive function and processing speed after controlling for gender, years of education and APOEε4 status. The effects of
rs541458 on resting state functional connectivity of the left superior parietal gyrus within left frontal-parietal network and gray matter volume of left middle temporal gyrus were modulated by age as well. Furthermore, the reduction of functional connectivity of superior parietal gyrus was closely related with better executive function in the T allele carriers-<65 years old group. And the increased volume of left middle temporal gyrus was significantly related with better executive function in the two CC genotype groups. Conclusions: Our results uncover the modulation of age on the PICALM rs541458’ effects on cognitive impairments and brain functional and structural measurements and may be beneficial for further genetic association studies.