Publications (5)148.02 Total impact
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Article: Increasing power for voxel-wise genome-wide association studies: The random field theory, least square kernel machines and fast permutation procedures.
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ABSTRACT: Imaging traits are thought to have more direct links to genetic variation than diagnostic measures based on cognitive or clinical assessments and provide a powerful substrate to examine the influence of genetics on human brains. Although imaging genetics has attracted growing attention and interest, most brain-wide genome-wide association studies focus on voxel-wise single-locus approaches, without taking advantage of the spatial information in images or combining the effect of multiple genetic variants. In this paper we present a fast implementation of voxel- and cluster-wise inferences based on the random field theory to fully use the spatial information in images. The approach is combined with a multi-locus model based on least square kernel machines to associate the joint effect of several single nucleotide polymorphisms (SNP) with imaging traits. A fast permutation procedure is also proposed which significantly reduces the number of permutations needed relative to the standard empirical method and provides accurate small p-value estimates based on parametric tail approximation. We explored the relation between 448,294 single nucleotide polymorphisms and 18,043 genes in 31,662 voxels of the entire brain across 740 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. We find method to be more sensitive compared with voxel-wise single-locus approaches. A number of genes were identified as having significant associations with volumetric changes. The most associated gene was GRIN2B, which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit and affects both the parietal and temporal lobes in human brains. Its role in Alzheimer's disease has been widely acknowledged and studied, suggesting the validity of the approach. The various advantages over existing approaches indicate a great potential offered by this novel framework to detect genetic influences on human brains.NeuroImage 07/2012; 63(2):858-73. · 5.89 Impact Factor -
Article: Identification of common variants associated with human hippocampal and intracranial volumes.
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ABSTRACT: Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).Nature Genetics 04/2012; 44(5):552-61. · 35.53 Impact Factor -
Article: Common variants at 12q14 and 12q24 are associated with hippocampal volume.
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ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.Nature Genetics 04/2012; 44(5):545-51. · 35.53 Impact Factor -
Article: Identification of common variants associated with human hippocampal and intracranial volumes
Nature Genetics 04/2012; 44(5):552-561. · 35.53 Impact Factor -
Article: Common variants at 12q14 and 12q24 are associated with hippocampal volume.
[show abstract] [hide abstract]
ABSTRACT: Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10 −7 . In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10 −11) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10 −11). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10 −7) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10 −7); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia. Differences in hippocampal volume that appear with advancing age represent cumulative effects of early-life factors, life-course events and disease. Hippocampal atrophy is a recognized biological marker of Alzheimer's disease 1,2 ; however, it is influenced by various vascular and metabolic factors 3,4 . Because hippocampal volume is a heritable 5 , widely measurable trait that shows meaningful detectable changes throughout life, it is a suitable endophenotype for aging-related physio-logical processes and presymptomatic diseases, improving the power to detect genetic associations. We explored genetic influences on hippocampal volume by conduct-ing a cross-sectional genome-wide association analysis in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 6 among 9,232 dementia-free persons from 8 community-based studies whose mean age ranged from 56 to 84 years (weighted average of 67.1 years). Each study imputed to a common set of SNPs from the Phase 2 HapMap Centre d'Etude du Polymorphisme Humain (CEPH) Utah residents of Northern and Western European ancestry (CEU) population using genotype data from Illumina or Affymetrix arrays; additive genetic models associating total hippocampal volume and genotype dosage were fitted with adjustment for age, sex and familial relationships (if applicable; Supplementary Note); and genomic control was applied. Study-specific results were combined in an inverse variance–weighted meta-analysis. We then conducted in silico replication of associations that reached genome-wide significance and sought additional evidence for sug-gestive associations in a second-stage targeted meta-analysis of 2,318 subjects from two community-based studies: the Three City Study and an independent sample from the third expansion of the Rotterdam Study. Characteristics of the discovery and replication samples are given (Supplementary Table 1). A Manhattan plot of −log 10 (P values) from the discovery analysis is shown (Fig. 1), where P values for 46 SNPs at 4 loci (Supplementary Table 2) surpassed our replication threshold of P < 4.0 × 10 −7 corres-ponding to 1 expected false positive. Of these, 18 SNPs at 2 loci sur-passed a genome-wide significance threshold of P < 5.0 × 10 −8 : the 12q14 locus, which included WIF1, LEMD3 and MSRB3, and the 12q24 locus, which included HRK and FBXW8. We found evidence of replication (P < 0.01) for both associations. The remaining sug-gestive associations included SNPs at 2q24 within DPP4 and at 9p33 within ASTN2, which had consistent directions of association in the discovery and replication phases but did not attain genome-wide sig-nificance in a combined analysis. Estimates for each stage are shown (Table 1). Discovery GWAS results for the region around each signal were annotated with recombination rates and known genes (Fig. 2), and study-specific findings are shown (Fig. 3).Nature Genetics 01/2012; 44(5):545-551. · 35.53 Impact Factor
