- Email: [email protected]
Genome-wide association of longitudinal volumetric mri measurements in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study
Alzheimer’s Imaging Consortium: IC-P-Poster Imaging of AD. In a population-based study of relatively young persons we investigated how these genetic loci associated with cognitive performance. In addition, we explored whether putative effects would be mediated by AD pathology and cerebral small vessel disease as seen on MRI. Methods: In 677 non-demented individuals (mean age: 67 yrs) from the populationbased Rotterdam Study, we genotyped reported significant SNPs from each locus (rs2075650, rs11136000, rs3851179, rs597668, rs744373 and rs3818361). All persons underwent cognitive testing, using a standardized test battery, and underwent MRI-scanning from which volumetric measures of grey matter, white matter, hippocampus and white matter lesions were obtained. Brain infarcts and cerebral microbleeds were rated visually. Persons with cortical infarcts were excluded. We investigated each SNP separately for its association with cognition and MRI-markers. Subsequently, we performed analyses with summary risk scores based on the six SNPs. These scores were constructed by weighting the number of risk alleles within an individual by the reported effect size for dementia. All analyses were adjusted for relevant confounders. Results: We found that rs744373 (BIN1) strongly associated with poorer memory performance (p ¼ 0.003, Bonferroni adjusted). None of the loci were significantly related to any of the MRI markers. Summary risk scores of the six loci together were neither associated with cognition nor with brain markers. Conclusions: In this study among a relatively young population, the BIN1 locus was strongly associated with poorer memory performance, while no associations with brain MRI markers were found. We hypothesize that BIN1 exerts its influence on the development of AD via mechanisms not visualized by structural MRI (e.g. amyloid-deposition or tau-pathology). Furthermore, we hypothesize that the effects of the other loci on AD possibly manifest at higher age.
IC-P-108
GENOME-WIDE ASSOCIATION OF LONGITUDINAL VOLUMETRIC MRI MEASUREMENTS IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) STUDY
S53
Table 1 The top 10 genes that are significantly associated with the atrophy of left hippocampus and left middle temporal lobe using GWAS with longitudinal ADNI data (P-value adjusted with Bonferroni correction) Left Hippocampus SNP
Chr Gene
rs2075650 19 rs9312873 5 rs17709449 14 rs16865111 2 rs12514030 5 rs6592155 11 rs2212602 21 rs3740868 11 rs245110 19 rs6040339 20
Left Middle Temporal Lobe Corrected SNP P-value
TOMM40 3.11E-12 ANKH 3.95E-11 FLRT2 6.81E-09 BC044918 2.25E-07 ANKH 3.55E-07 DLG2 1.97E-06 ERG 2.23E-06 GPR83 2.59E-06 VRK3 3.14E-06 JAG1 6.82E-06
Chr Gene
rs2075650 19 rs439401 19 rs2228603 19 rs12610185 19 rs2304128 19 rs10827512 10 rs10868467 9 rs10758455 9 rs993248 5 rs1550985 2
Corrected P-value
TOMM40 1.00E-17 APOE 2.96E-16 NCAN 4.61E-15 PBX4 6.09E-14 GMIP 2.18E-13 CCNY 4.82E-11 GAS1 1.01E-08 FRMPD1 1.03E-08 NBPF22P 1.61E-08 DPP10 2.53E-08
gene: TOMM40, P-value ¼ 7.78E-09), GWAS analysis of the longitudinal MRI measurements identified not only the well established genetic variants in the TOMM40/APOE region, but also revealed a rich list of potential SNPs associated with the rate of brain atrophy. This finding suggests that the longitudinal model in GWAS can greatly improve the statistical power with even small sample sizes because of the inclusion of data collected over time. We plan to validate these discovered genetic variants in additional studies using larger cohorts.
IC-P-109
THE EFFECT OF APOLIPOPROTEIN E POLYMORPHISM ON HIPPOCAMPAL MORPHOLOGY IN THE PATIENTS WITH LATEONSET DEPRESSION
Jia Sun1, Laura Nisenbaum2, Robert Dean2, Mark Farmen2, Kalpana Merchant2, Michael Hutton3, Peng Yu2, 1The University of Texas School of Public Health, Houston, Texas, United States; 2Eli Lilly and Company, Indianapolis, Indiana, United States; 3Eli Lilly and Company, Windlesham, United Kingdom.
Hyun-Kook Lim1, Chang Uk Lee2, 1Department of Psychiatry, The Catholic University of Korea, Suwon, South Korea; 2Department of Psychiatry, The Catholic Univerisity of Korea, Seoul, South Korea.
Background: Several recent genome-wide studies have investigated genetic association with neuroimaging phenotypic traits for identifying genetic variants related to Alzheimer’s disease. Although ADNI is a longitudinal study, these previous analyses have focused on genetic association with cross-sectional phenotypes rather than the variation of those traits over time. To take advantage of the longitudinal nature of the ADNI dataset, we applied a mixed model to find genetic variations associated with changes of MRIdefined brain structures. Methods: We used ADNI data published in Jan-2011. Over 500K SNPs in 733 non-Hispanic Caucasians (AD, HC, and MCI) were analyzed. GWAS was performed using a linear mixed model with MRI volumes, including Left Hippocampus (LH) and Left Middle Temporal (LMIDTEMP) lobe measured by UCSD (best performance in power analysis), at all available visits (baseline to 36 months). Our longitudinal model also includes the time elapsed since baseline, quadratic time, SNP (additive), SNP and time interaction, random intercept, and covariates such as age, gender, education, and ICV. We reported the P-value of the interaction term between SNP and time (adjusted with Bonferroni correction) since it reflects whether the rate of atrophy is different among genotypic groups. Results: Of all SNPs examined, 428 SNPs were significantly (P-value < 0.05 after Bonferroni correction) associated with the rate of LH atrophy, and TOMM40 is ranked the highest (corrected P-value ¼ 3.11E-12). 950 SNPs were significantly associated with the LMIDTEMP lobe (Table 1); TOMM40 exhibited the greatest significance (corrected Pvalue ¼ 1.00E-17), followed by APOE. 31 SNPs were selected with both structures (top genes: TOMM40/APOE). Finally, the APOE-e4 allele was also associated with both LH and LMIDTEMP lobe (P-value < E-29). Conclusions: Compared with GWAS using baseline LH volume (top
Background: The apolipoprotein E (APOE) gene and late onset depression (LOD) have been considered as well established risk factor for Alzheimer’s disease (AD). The hippocampus is particularly vulnerable to damage at the very earliest stages of AD and LOD. The aim of this study is to evaluate the effect of APOE polymorphism on hippocampal morphology in LOD. We hypothesized that there may be a synergistic effect of LOD and APOE e4 on the hippocampal shape alteration. Methods: All subjects were ethnically Korean. 3T MR images were acquired from 30 LOD patients without APOE e4, 28 LOD patients with APOE e3/e4, 19 LOD patients with APOE e4/e4 and 30 age - and sex-matched healthy control subjects. Individual hippocampal measures were obtained using FMRIB’s Integrated Registration and Segmentation Tool (FIRST), an automatic subcortical segmentation program. Boundary correction was used for the classification of the boundary voxels. Regional changes of bilateral hippocampal morphology were characterized using vertex analysis of FIRST. Results: As compared to LOD patients without APOE e4, LOD patients with APOE e3/e4 showed significant deformations in the CA1 region of right hippocampus. Moreover, APOE e4/e4 patients showed more extensive shape deformations in the CA1 region of right compared with those in APOE e3/e4 patients. There were also some changes in the CA2-4 subregions of the right hippocampus among LOD patients with APOE e4. On the other hand, the CA 2-4 areas and the subiculum of right hippocampal surface of the LOD patients without APOE e4 showed significant shape deformation compared with those in healthy control subjects. On the contrary to the previous studies conducted in the western countries, the right hippocampal shape deformations were more extensive than the left. Conclusions: The APOE e4 gene have increased the hippocampal shape deformation in dose-dependent fashion in LOD.
IC-P-108
GENOME-WIDE ASSOCIATION OF LONGITUDINAL VOLUMETRIC MRI MEASUREMENTS IN THE ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI) STUDY
S53
Table 1 The top 10 genes that are significantly associated with the atrophy of left hippocampus and left middle temporal lobe using GWAS with longitudinal ADNI data (P-value adjusted with Bonferroni correction) Left Hippocampus SNP
Chr Gene
rs2075650 19 rs9312873 5 rs17709449 14 rs16865111 2 rs12514030 5 rs6592155 11 rs2212602 21 rs3740868 11 rs245110 19 rs6040339 20
Left Middle Temporal Lobe Corrected SNP P-value
TOMM40 3.11E-12 ANKH 3.95E-11 FLRT2 6.81E-09 BC044918 2.25E-07 ANKH 3.55E-07 DLG2 1.97E-06 ERG 2.23E-06 GPR83 2.59E-06 VRK3 3.14E-06 JAG1 6.82E-06
Chr Gene
rs2075650 19 rs439401 19 rs2228603 19 rs12610185 19 rs2304128 19 rs10827512 10 rs10868467 9 rs10758455 9 rs993248 5 rs1550985 2
Corrected P-value
TOMM40 1.00E-17 APOE 2.96E-16 NCAN 4.61E-15 PBX4 6.09E-14 GMIP 2.18E-13 CCNY 4.82E-11 GAS1 1.01E-08 FRMPD1 1.03E-08 NBPF22P 1.61E-08 DPP10 2.53E-08
gene: TOMM40, P-value ¼ 7.78E-09), GWAS analysis of the longitudinal MRI measurements identified not only the well established genetic variants in the TOMM40/APOE region, but also revealed a rich list of potential SNPs associated with the rate of brain atrophy. This finding suggests that the longitudinal model in GWAS can greatly improve the statistical power with even small sample sizes because of the inclusion of data collected over time. We plan to validate these discovered genetic variants in additional studies using larger cohorts.
IC-P-109
THE EFFECT OF APOLIPOPROTEIN E POLYMORPHISM ON HIPPOCAMPAL MORPHOLOGY IN THE PATIENTS WITH LATEONSET DEPRESSION
Jia Sun1, Laura Nisenbaum2, Robert Dean2, Mark Farmen2, Kalpana Merchant2, Michael Hutton3, Peng Yu2, 1The University of Texas School of Public Health, Houston, Texas, United States; 2Eli Lilly and Company, Indianapolis, Indiana, United States; 3Eli Lilly and Company, Windlesham, United Kingdom.
Hyun-Kook Lim1, Chang Uk Lee2, 1Department of Psychiatry, The Catholic University of Korea, Suwon, South Korea; 2Department of Psychiatry, The Catholic Univerisity of Korea, Seoul, South Korea.
Background: Several recent genome-wide studies have investigated genetic association with neuroimaging phenotypic traits for identifying genetic variants related to Alzheimer’s disease. Although ADNI is a longitudinal study, these previous analyses have focused on genetic association with cross-sectional phenotypes rather than the variation of those traits over time. To take advantage of the longitudinal nature of the ADNI dataset, we applied a mixed model to find genetic variations associated with changes of MRIdefined brain structures. Methods: We used ADNI data published in Jan-2011. Over 500K SNPs in 733 non-Hispanic Caucasians (AD, HC, and MCI) were analyzed. GWAS was performed using a linear mixed model with MRI volumes, including Left Hippocampus (LH) and Left Middle Temporal (LMIDTEMP) lobe measured by UCSD (best performance in power analysis), at all available visits (baseline to 36 months). Our longitudinal model also includes the time elapsed since baseline, quadratic time, SNP (additive), SNP and time interaction, random intercept, and covariates such as age, gender, education, and ICV. We reported the P-value of the interaction term between SNP and time (adjusted with Bonferroni correction) since it reflects whether the rate of atrophy is different among genotypic groups. Results: Of all SNPs examined, 428 SNPs were significantly (P-value < 0.05 after Bonferroni correction) associated with the rate of LH atrophy, and TOMM40 is ranked the highest (corrected P-value ¼ 3.11E-12). 950 SNPs were significantly associated with the LMIDTEMP lobe (Table 1); TOMM40 exhibited the greatest significance (corrected Pvalue ¼ 1.00E-17), followed by APOE. 31 SNPs were selected with both structures (top genes: TOMM40/APOE). Finally, the APOE-e4 allele was also associated with both LH and LMIDTEMP lobe (P-value < E-29). Conclusions: Compared with GWAS using baseline LH volume (top
Background: The apolipoprotein E (APOE) gene and late onset depression (LOD) have been considered as well established risk factor for Alzheimer’s disease (AD). The hippocampus is particularly vulnerable to damage at the very earliest stages of AD and LOD. The aim of this study is to evaluate the effect of APOE polymorphism on hippocampal morphology in LOD. We hypothesized that there may be a synergistic effect of LOD and APOE e4 on the hippocampal shape alteration. Methods: All subjects were ethnically Korean. 3T MR images were acquired from 30 LOD patients without APOE e4, 28 LOD patients with APOE e3/e4, 19 LOD patients with APOE e4/e4 and 30 age - and sex-matched healthy control subjects. Individual hippocampal measures were obtained using FMRIB’s Integrated Registration and Segmentation Tool (FIRST), an automatic subcortical segmentation program. Boundary correction was used for the classification of the boundary voxels. Regional changes of bilateral hippocampal morphology were characterized using vertex analysis of FIRST. Results: As compared to LOD patients without APOE e4, LOD patients with APOE e3/e4 showed significant deformations in the CA1 region of right hippocampus. Moreover, APOE e4/e4 patients showed more extensive shape deformations in the CA1 region of right compared with those in APOE e3/e4 patients. There were also some changes in the CA2-4 subregions of the right hippocampus among LOD patients with APOE e4. On the other hand, the CA 2-4 areas and the subiculum of right hippocampal surface of the LOD patients without APOE e4 showed significant shape deformation compared with those in healthy control subjects. On the contrary to the previous studies conducted in the western countries, the right hippocampal shape deformations were more extensive than the left. Conclusions: The APOE e4 gene have increased the hippocampal shape deformation in dose-dependent fashion in LOD.