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15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

https://arctichealth.org/en/permalink/ahliterature287813
Source
Transl Psychiatry. 2017 Apr 25;7(4):e1109
Publication Type
Article
Date
Apr-25-2017
Author
M O Ulfarsson
G B Walters
O. Gustafsson
S. Steinberg
A. Silva
O M Doyle
M. Brammer
D F Gudbjartsson
S. Arnarsdottir
G A Jonsdottir
R S Gisladottir
G. Bjornsdottir
H. Helgason
L M Ellingsen
J G Halldorsson
E. Saemundsen
B. Stefansdottir
L. Jonsson
V K Eiriksdottir
G R Eiriksdottir
G H Johannesdottir
U. Unnsteinsdottir
B. Jonsdottir
B B Magnusdottir
P. Sulem
U. Thorsteinsdottir
E. Sigurdsson
D. Brandeis
A. Meyer-Lindenberg
H. Stefansson
K. Stefansson
Source
Transl Psychiatry. 2017 Apr 25;7(4):e1109
Date
Apr-25-2017
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Chromosome Aberrations
Chromosome Deletion
Chromosomes, Human, Pair 15 - genetics
Cognition - physiology
DNA Copy Number Variations - genetics
Developmental Disabilities - genetics
Dyscalculia - genetics
Dyslexia - genetics
Female
Functional Neuroimaging - methods - standards
Heterozygote
Humans
Iceland - epidemiology
Intellectual Disability - genetics
Magnetic Resonance Imaging - methods
Male
Middle Aged
Neuropsychological Tests - standards
Phenotype
Temporal Lobe - anatomy & histology - diagnostic imaging
Young Adult
Abstract
Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.
Notes
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PubMed ID
28440815 View in PubMed
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Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population.

https://arctichealth.org/en/permalink/ahliterature176678
Source
Am J Hum Genet. 2005 Mar;76(3):505-9
Publication Type
Article
Date
Mar-2005
Author
A. Helgadottir
S. Gretarsdottir
D. St Clair
A. Manolescu
J. Cheung
G. Thorleifsson
A. Pasdar
S F A Grant
L J Whalley
H. Hakonarson
U. Thorsteinsdottir
A. Kong
J. Gulcher
K. Stefansson
M J MacLeod
Author Affiliation
deCODE Genetics, Reykjavik, Iceland.
Source
Am J Hum Genet. 2005 Mar;76(3):505-9
Date
Mar-2005
Language
English
Publication Type
Article
Keywords
5-Lipoxygenase-Activating Proteins
Aged
Carrier Proteins - genetics
Case-Control Studies
Female
Gene Frequency
Genetic Variation
Genotype
Haplotypes
Humans
Iceland
Male
Membrane Proteins - genetics
Middle Aged
Polymorphism, Single Nucleotide
Risk factors
Scotland
Stroke - genetics
Abstract
Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.
Notes
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PubMed ID
15640973 View in PubMed
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A common biological basis of obesity and nicotine addiction.

https://arctichealth.org/en/permalink/ahliterature106935
Source
Transl Psychiatry. 2013;3:e308
Publication Type
Article
Date
2013
Author
T E Thorgeirsson
D F Gudbjartsson
P. Sulem
S. Besenbacher
U. Styrkarsdottir
G. Thorleifsson
G B Walters
H. Furberg
P F Sullivan
J. Marchini
M I McCarthy
V. Steinthorsdottir
U. Thorsteinsdottir
K. Stefansson
Author Affiliation
Decode genetics/AMGEN, Sturlugata 8, Reykjavik, Iceland.
Source
Transl Psychiatry. 2013;3:e308
Date
2013
Language
English
Publication Type
Article
Keywords
Age of Onset
Behavior, Addictive - genetics
Body mass index
Humans
Iceland - epidemiology
Obesity - genetics
Polymorphism, Single Nucleotide
Smoking - epidemiology - genetics
Tobacco Use Disorder - genetics
Abstract
Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 ? 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 ? 10(-5)) and CPD (P=9.3 ? 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
Notes
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PubMed ID
24084939 View in PubMed
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A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

https://arctichealth.org/en/permalink/ahliterature279141
Source
Mol Psychiatry. 2016 May;21(5):594-600
Publication Type
Article
Date
May-2016
Author
T E Thorgeirsson
S. Steinberg
G W Reginsson
G. Bjornsdottir
T. Rafnar
I. Jonsdottir
A. Helgadottir
S. Gretarsdottir
H. Helgadottir
S. Jonsson
S E Matthiasson
T. Gislason
T. Tyrfingsson
T. Gudbjartsson
H J Isaksson
H. Hardardottir
A. Sigvaldason
L A Kiemeney
A. Haugen
S. Zienolddiny
H J Wolf
W A Franklin
A. Panadero
J I Mayordomo
I P Hall
E. Rönmark
B. Lundbäck
A. Dirksen
H. Ashraf
J H Pedersen
G. Masson
P. Sulem
U. Thorsteinsdottir
D F Gudbjartsson
K. Stefansson
Source
Mol Psychiatry. 2016 May;21(5):594-600
Date
May-2016
Language
English
Publication Type
Article
Keywords
Adolescent
Adult
Aged
Aged, 80 and over
Aortic Aneurysm, Abdominal - etiology - genetics
European Continental Ancestry Group - genetics
Female
Genetic Association Studies
Genetic Predisposition to Disease
Humans
Iceland
Lung Neoplasms - etiology - genetics
Male
Middle Aged
Mutation, Missense
Peripheral Arterial Disease - etiology - genetics
Pulmonary Disease, Chronic Obstructive - etiology - genetics
Receptors, Nicotinic - genetics
Smoking - genetics
Tobacco Use Disorder - complications - genetics
Young Adult
Abstract
Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human a4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
PubMed ID
26952864 View in PubMed
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