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1. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author

Ibrahim-Verbaas, CA, Bressler, J, Debette, S, Schuur, M, Smith, AV, Bis, JC, Davies, G, Trompet, S, Smith, JA, Wolf, C, Chibnik, LB, Liu, Y, Vitart, V, Kirin, M, Petrovic, K, Polasek, O, Zgaga, L, Fawns-Ritchie, C, Hoffmann, P, Karjalainen, J, Lahti, J, Llewellyn, DJ, Schmidt, CO, Mather, KA, Chouraki, V, Sun, Q, Resnick, SM, Rose, LM, Oldmeadow, C, Stewart, M, Smith, BH, Gudnason, V, Yang, Q, Mirza, SS, Jukema, JW, deJager, PL, Harris, TB, Liewald, DC, Amin, N, Coker, LH, Stegle, O, Lopez, OL, Schmidt, R, Teumer, A, Ford, I, Karbalai, N, Becker, JT, Jonsdottir, MK, Au, R, Fehrmann, RSN, Herms, S, Nalls, M, Zhao, W, Turner, ST, Yaffe, K, Lohman, K, van Swieten, JC, Kardia, SLR, Knopman, DS, Meeks, WM, Heiss, G, Holliday, EG, Schofield, PW, Tanaka, T, Stott, DJ, Wang, J, Ridker, P, Gow, AJ, Pattie, A, Starr, JM, Hocking, LJ, Armstrong, NJ, McLachlan, S, Shulman, JM, Pilling, LC, Eiriksdottir, G, Scott, RJ, Kochan, NA, Palotie, A, Hsieh, Y-C, Eriksson, JG, Penman, A, Gottesman, RF, Oostra, BA, Yu, L, DeStefano, AL, Beiser, A, Garcia, M, Rotter, JI, Nöthen, MM, Hofman, A, Slagboom, PE, Westendorp, RGJ, Buckley, BM, Wolf, PA, Uitterlinden, AG, Psaty, BM, Grabe, HJ, Bandinelli, S, and Chasman, DI

Subjects
Biological Psychology, Clinical and Health Psychology, Psychology, Genetics, Basic Behavioral and Social Science, Aging, Human Genome, Brain Disorders, Behavioral and Social Science, Mental Health, Neurosciences, Aged, Aged, 80 and over, Cell Adhesion Molecules, Cognition, Cohort Studies, Executive Function, Female, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genomics, Humans, Introns, Male, Middle Aged, Neuropsychological Tests, Polymorphism, Single Nucleotide, White People, gamma-Aminobutyric Acid, Generation Scotland, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Clinical sciences, Biological psychology, Clinical and health psychology
Abstract

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Published
2016

2. Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

Author

Davies, G, Armstrong, N, Bis, JC, Bressler, J, Chouraki, V, Giddaluru, S, Hofer, E, Ibrahim-Verbaas, CA, Kirin, M, Lahti, J, van der Lee, SJ, Le Hellard, S, Liu, T, Marioni, RE, Oldmeadow, C, Postmus, I, Smith, AV, Smith, JA, Thalamuthu, A, Thomson, R, Vitart, V, Wang, J, Yu, L, Zgaga, L, Zhao, W, Boxall, R, Harris, SE, Hill, WD, Liewald, DC, Luciano, M, Adams, H, Ames, D, Amin, N, Amouyel, P, Assareh, AA, Au, R, Becker, JT, Beiser, A, Berr, C, Bertram, L, Boerwinkle, E, Buckley, BM, Campbell, H, Corley, J, De Jager, PL, Dufouil, C, Eriksson, JG, Espeseth, T, Faul, JD, Ford, I, Generation Scotland, Gottesman, RF, Griswold, ME, Gudnason, V, Harris, TB, Heiss, G, Hofman, A, Holliday, EG, Huffman, J, Kardia, SLR, Kochan, N, Knopman, DS, Kwok, JB, Lambert, J-C, Lee, T, Li, G, Li, S-C, Loitfelder, M, Lopez, OL, Lundervold, AJ, Lundqvist, A, Mather, KA, Mirza, SS, Nyberg, L, Oostra, BA, Palotie, A, Papenberg, G, Pattie, A, Petrovic, K, Polasek, O, Psaty, BM, Redmond, P, Reppermund, S, Rotter, JI, Schmidt, H, Schuur, M, Schofield, PW, Scott, RJ, Steen, VM, Stott, DJ, van Swieten, JC, Taylor, KD, Trollor, J, Trompet, S, Uitterlinden, AG, Weinstein, G, Widen, E, Windham, BG, Jukema, JW, and Wright, AF

Subjects
Generation Scotland, Humans, Genetic Predisposition to Disease, HMGN1 Protein, Cohort Studies, Cognition, Cognition Disorders, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Scotland, Female, Male, Atherosclerosis, Genome-Wide Association Study, and over, Polymorphism, Single Nucleotide, Psychiatry, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015

3. Genetic contributions to variation in general cognitive function:a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53 949)

Author

Davies, G., Armstrong, N., Bis, J. C., Bressler, J., Chouraki, V., Giddaluru, S., Hofer, E., Ibrahim-Verbaas, C. A., Kirin, M., Lahti, J., van der Lee, S. J., Le Hellard, S., Liu, T., Marioni, R. E., Oldmeadow, C., Postmus, I., Smith, A. V., Smith, J. A., Thalamuthu, A., Thomson, R., Vitart, V., Wang, J., Yu, L., Zgaga, L., Zhao, W., Boxall, R., Harris, S. E., Hill, W. D., Liewald, D. C., Luciano, M., Adams, H., Ames, D., Amin, N., Amouyel, P., Assareh, A. A., Au, R., Becker, J. T., Beiser, A., Berr, C., Bertram, L., Boerwinkle, E., Buckley, B. M., Campbell, H., Corley, J., De Jager, P. L., Dufouil, C., Eriksson, J. G., Espeseth, T., Faul, J. D., Ford, I., Gottesman, R. F., Griswold, M. E., Gudnason, V., Harris, T. B., Heiss, G., Hofman, A., Holliday, E. G., Huffman, J., Kardia, S. L. R., Kochan, N., Knopman, D. S., Kwok, J. B., Lambert, J-C, Lee, T., Li, G., Li, S-C, Loitfelder, M., Lopez, O. L., Lundervold, A. J., Lundquist, Anders, Mather, K. A., Mirza, S. S., Nyberg, Lars, Oostra, B. A., Palotie, A., Papenberg, G., Pattie, A., Petrovic, K., Polasek, O., Psaty, B. M., Redmond, P., Reppermund, S., Rotter, J. I., Schmidt, H., Schuur, M., Schofield, P. W., Scott, R. J., Steen, V. M., Stott, D. J., Van Swieten, J. C., Taylor, K. D., Trollor, J., Trompet, S., Uitterlinden, A. G., Weinstein, G., Widen, E., Windham, B. G., Jukema, J. W., Wright, A. F., Wright, M. J., Yang, Q., Amieva, H., Attia, J. R., Bennett, D. A., Brodaty, H., de Craen, A. J. M., Hayward, C., Ikram, M. A., Lindenberger, U., Nilsson, Lars-Göran, Porteous, D. J., Raikkonen, K., Reinvang, I., Rudan, I., Sachdev, P. S., Schmidt, R., Schofield, P. R., Srikanth, V., Starr, J. M., Turner, S. T., Weir, D. R., Wilson, J. F., Van Duijn, C., Launer, L., Fitzpatrick, A. L., Seshadri, S., Jr, T. H. Mosley, Deary, I. J., Epidemiology, Neurology, Radiology & Nuclear Medicine, Clinical Genetics, and Internal Medicine

Subjects
Male, Neurologi, SUSCEPTIBILITY LOCI, Neuropsychological Tests, Polymorphism, Single Nucleotide, IDENTIFIES VARIANTS, APOLIPOPROTEIN-E, Cohort Studies, Cognition, OLD-AGE, SDG 3 - Good Health and Well-being, Humans, Genetic Predisposition to Disease, HUMAN INTELLIGENCE, Aged, TYPE-4 ALLELE, Aged, 80 and over, TEST BATTERIES, Middle Aged, Atherosclerosis, CPG-BINDING PROTEIN-2, ALZHEIMERS-DISEASE, Phenotype, Scotland, Neurology, Female, Cognition Disorders, Immediate Communication, HUMAN HEIGHT, HMGN1 Protein, Genome-Wide Association Study
Abstract

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53 949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10−9, MIR2113; rs17522122, P=2.55 × 10−8, AKAP6; rs10119, P=5.67 × 10−9, APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10−6). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10−17). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer’s disease: TOMM40, APOE, ABCG1 and MEF2C.

Published
2015
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4. Rivastigmine in outpatient services: experience of 114 neurologists in Austria

Author

Petrovic K, Reinhold Schmidt, and Lechner A

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Phenylcarbamates, Rivastigmine, Neuropsychological Tests, Central nervous system disease, Cognition, Alzheimer Disease, Internal medicine, Outpatients, medicine, Humans, Pharmacology (medical), Dosing, Effects of sleep deprivation on cognitive performance, Adverse effect, Aged, Aged, 80 and over, Psychiatric Status Rating Scales, Chemotherapy, business.industry, medicine.disease, Surgery, Clinical trial, Psychiatry and Mental health, Neuroprotective Agents, Treatment Outcome, Austria, Disease Progression, Female, Carbamates, Alzheimer's disease, business, medicine.drug
Abstract

We performed an open-label study in Alzheimer patients on the use of rivastigmine in clinical routine. We evaluated the mode of dosing, safety and response to treatment over 24 weeks in 529 Alzheimer patients recruited by 114 neurologists. At the start of the study, and after 12 and 24 weeks, the participants were tested with the Mini-Mental State Examination and the Global Deterioration Scale. Titration of rivastigmine was slower than expected: After 2 weeks, only 41.8% of subjects received an effective daily dose of at least 6 mg. A total of 33.8% of patients experienced 305 mostly transient adverse events of mild or moderate intensity. Gastrointestinal symptoms occurred in 30.4% of subjects and symptoms of the nervous system in 16.4%. Similar to controlled trials, the cognitive performance of patients improved, with more than 60% of subjects showing improvement from baseline on the Mini-Mental State Examination by week 24. More than 40% of patients showed improvement on the Global Deterioration Scale. This study suggests that, in daily clinical practice, titration of rivastigmine deviates from the prescribing information. Under routine conditions, the safety profile of the drug is favourable, as is the response to treatment.

Published
2002
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