Browsing by Author "AddNeuroMed Consortium"

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    Genetic associations with psychosis and affective disturbance in Alzheimer's disease
    (Wiley, 2024-05-23) Antonsdottir, Inga Margret; Creese, Byron; Klei, Lambertus; DeMichele-Sweet, Mary Ann A.; Weamer, Elise A.; Garcia-Gonzalez, Pablo; Marquie, Marta; Boada, Mercè; Alarcón-Martín, Emilio; Valero, Sergi; NIA-LOAD Family Based Study Consortium; Alzheimer's Disease Genetics Consortium (ADGC); AddNeuroMed Consortium; Liu, Yushi; Hooli, Basavaraj; Aarsland, Dag; Selbaek, Geir; Bergh, Sverre; Rongve, Arvid; Saltvedt, Ingvild; Skjellegrind, Håvard K.; Engdahl, Bo; Andreassen, Ole A.; Borroni, Barbara; Mecocci, Patrizia; Wedatilake, Yehani; Mayeux, Richard; Foroud, Tatiana; Ruiz, Agustín; Lopez, Oscar L.; Kamboh, M. Ilyas; Ballard, Clive; Devlin, Bernie; Lyketsos, Constantine; Sweet, Robert A.; Medical and Molecular Genetics, School of Medicine
    Introduction: Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. Methods: Genome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). Results: AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. Discussion: AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development. Highlights: It has long been known that psychotic and affective symptoms are often comorbid in individuals diagnosed with Alzheimer's disease. Here we examined for the first time the genetic architecture underlying this clinical observation, determining that psychotic and affective phenotypes in Alzheimer's disease are genetically correlated. Nevertheless, psychotic and affective phenotypes in Alzheimer's disease diverged in their genetic correlations with psychiatric phenotypes assessed in individuals without Alzheimer's disease. Psychosis in Alzheimer's disease was negatively genetically correlated with bipolar disorder and positively with depressive symptoms, whereas the affective phenotypes in Alzheimer's disease were positively correlated with anxiety disorder and more strongly correlated than psychosis with depressive symptoms. Psychosis in Alzheimer's disease, and the joint psychotic and affective phenotype, had significant estimated heritability, whereas the affective in AD did not. Examination of the loci most strongly associated with the psychotic, affective, or joint phenotypes revealed overlapping and unique associations.
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    Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics
    (Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
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    Immunity gene IFITM3 variant: Relation to cognition and Alzheimer's disease pathology
    (Alzheimer’s Association, 2022-06-21) Pyun, Jung-Min; Park, Young Ho; Hodges, Angela; Jang, Jae-Won; Bice, Paula J.; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; AddNeuroMed Consortium; Alzheimer's Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
    Introduction: We investigated single-nucleotide polymorphisms (SNPs) in IFITM3, an innate immunity gene and modulator of amyloid beta in Alzheimer's disease (AD), for association with cognition and AD biomarkers. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1565) and AddNeuroMed (N = 633) as discovery and replication samples, respectively. We performed gene-based association analysis of SNPs in IFITM3 with cognitive performance and SNP-based association analysis with cognitive decline and amyloid, tau, and neurodegeneration biomarkers for AD. Results: Gene-based association analysis showed that IFITM3 was significantly associated with cognitive performance. Particularly, rs10751647 in IFITM3 was associated with less cognitive decline, less amyloid and tau burden, and less brain atrophy in ADNI. The association of rs10751647 with cognitive decline and brain atrophy was replicated in AddNeuroMed. Discussion: This suggests that rs10751647 in IFITM3 is associated with less vulnerability for cognitive decline and AD biomarkers, providing mechanistic insight regarding involvement of immunity and infection in AD. Highlights: IFITM3 is significantly associated with cognitive performance.rs10751647 in IFITM3 is associated with cognitive decline rates with replication.rs10751647 is associated with amyloid beta load, cerebrospinal fluid phosphorylated tau levels, and brain atrophy.rs10751647 is associated with IFITM3 expression levels in blood and brain.rs10751647 in IFITM3 is related to less vulnerability to Alzheimer's disease pathogenesis.
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    Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment
    (Springer Nature, 2013) Nho, K.; Corneveaux, J. J.; Kim, S.; Lin, H.; Risacher, S. L.; Shen, L.; Swaminathan, S.; Ramanan, V. K.; Liu, Y.; Foroud, T.; Inlow, M. H.; Siniard, A. L.; Reiman, R. A.; Aisen, P. S.; Petersen, R. C.; Green, R. C.; Jack, C. R.; Weiner, M. W.; Baldwin, C. T.; Lunetta, K.; Farrer, L. A.; Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study; Furney, S. J.; Lovestone, S.; Simmons, A.; Mecocci, P.; Vellas, B.; Tsolaki, M.; Kloszewska, I.; Soininen, H.; AddNeuroMed Consortium; McDonald, B. C.; Farlow, M. R.; Ghetti, B.; Indiana Memory and Aging Study; Huentelman, M. J.; Saykin, A. J.; Alzheimer's Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
    Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.