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PMID: 22888310 Published · epublish English Journal Article

Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression.

Frontiers in neuroscience ·Vol. 6 ·2012-00-00 ·Pages 115

Kohannim O, Hibar DP, Stein JL, Jahanshad N, Hua X, Rajagopalan P, Toga AW, Jack CR, Weiner MW, de Zubicaray GI, McMahon KL, Hansell NK, Martin NG, Wright MJ, Thompson PM, Alzheimer’s Disease Neuroimaging Initiative

Abstract

We implemented least absolute shrinkage and selection operator (LASSO) regression to evaluate gene effects in genome-wide association studies (GWAS) of brain images, using an MRI-derived temporal lobe volume measure from 729 subjects scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sparse groups of SNPs in individual genes were selected by LASSO, which identifies efficient sets of variants influencing the data. These SNPs were considered jointly when assessing their association with neuroimaging measures. We discovered 22 genes that passed genome-wide significance for influencing temporal lobe volume. This was a substantially greater number of significant genes compared to those found with standard, univariate GWAS. These top genes are all expressed in the brain and include genes previously related to brain function or neuropsychiatric disorders such as MACROD2, SORCS2, GRIN2B, MAGI2, NPAS3, CLSTN2, GABRG3, NRXN3, PRKAG2, GAS7, RBFOX1, ADARB2, CHD4, and CDH13. The top genes we identified with this method also displayed significant and widespread post hoc effects on voxelwise, tensor-based morphometry (TBM) maps of the temporal lobes. The most significantly associated gene was an autism susceptibility gene known as MACROD2. We were able to successfully replicate the effect of the MACROD2 gene in an independent cohort of 564 young, Australian healthy adult twins and siblings scanned with MRI (mean age: 23.8 ± 2.2 SD years). Our approach powerfully complements univariate techniques in detecting influences of genes on the living brain.

Keywords
GWAS LASSO MACROD2 MRI imaging genetics neuroimaging
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Kohannim Omid
Imaging Genetics Center at the Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine Los Angeles, CA, USA.
Hibar Derrek P
Stein Jason L
Jahanshad Neda
Hua Xue
Rajagopalan Priya
Toga Arthur W
Jack Clifford R
Weiner Michael W
de Zubicaray Greig I
McMahon Katie L
Hansell Narelle K
Martin Nicholas G
Wright Margaret J
Thompson Paul M
Alzheimer’s Disease Neuroimaging Initiative
References (80)
80 references, click to expand
  1. Genetic model testing and statistical power in population-based association studies of quantitative traits.
    Genet Epidemiol. 2007 May;31(4):358-62 PMID: 17352422
  2. The Bayesian lasso for genome-wide association studies.
    Bioinformatics. 2011 Feb 15;27(4):516-23 PMID: 21156729
  3. SNP selection in genome-wide and candidate gene studies via penalized logistic regression.
    Genet Epidemiol. 2010 Dec;34(8):879-91 PMID: 21104890
  4. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
    Science. 1993 Aug 13;261(5123):921-3 PMID: 8346443
  5. Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene.
    Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):E851-9 PMID: 22232660
  6. Identification of common variants associated with human hippocampal and intracranial volumes.
    Nat Genet. 2012 Apr 15;44(5):552-61 PMID: 22504417
  7. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.
    Am J Hum Genet. 2009 Jan;84(1):35-43 PMID: 19118814
  8. Common vs. rare allele hypotheses for complex diseases.
    Curr Opin Genet Dev. 2009 Jun;19(3):212-9 PMID: 19481926
  9. Tensor-based morphometry as a neuroimaging biomarker for Alzheimer's disease: an MRI study of 676 AD, MCI, and normal subjects.
    Neuroimage. 2008 Nov 15;43(3):458-69 PMID: 18691658
  10. Sparse reduced-rank regression detects genetic associations with voxel-wise longitudinal phenotypes in Alzheimer's disease.
    Neuroimage. 2012 Mar;60(1):700-16 PMID: 22209813
  11. Regularization Paths for Generalized Linear Models via Coordinate Descent.
    J Stat Softw. 2010;33(1):1-22 PMID: 20808728
  12. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.
    Science. 2007 May 11;316(5826):889-94 PMID: 17434869
  13. A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population.
    Am J Hum Genet. 2007 Jul;81(1):17-31 PMID: 17564960
  14. Common Kibra alleles are associated with human memory performance.
    Science. 2006 Oct 20;314(5798):475-8 PMID: 17053149
  15. A nonparametric method for automatic correction of intensity nonuniformity in MRI data.
    IEEE Trans Med Imaging. 1998 Feb;17(1):87-97 PMID: 9617910
  16. Mini-Mental State Examination (MMSE).
    Psychopharmacol Bull. 1988;24(4):689-92 PMID: 3249771
  17. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
    Nat Genet. 2009 Oct;41(10):1088-93 PMID: 19734902
  18. Identifying quantitative trait loci via group-sparse multitask regression and feature selection: an imaging genetics study of the ADNI cohort.
    Bioinformatics. 2012 Jan 15;28(2):229-37 PMID: 22155867
  19. Twelve-month metabolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: findings from the Alzheimer's Disease Neuroimaging Initiative.
    Neuroimage. 2010 Jun;51(2):654-64 PMID: 20202480
  20. Simultaneous genome-wide association studies of anti-cyclic citrullinated peptide in rheumatoid arthritis using penalized orthogonal-components regression.
    BMC Proc. 2009 Dec 15;3 Suppl 7:S20 PMID: 20018010
  21. Intermediate phenotypes and genetic mechanisms of psychiatric disorders.
    Nat Rev Neurosci. 2006 Oct;7(10):818-27 PMID: 16988657
  22. Joint identification of multiple genetic variants via elastic-net variable selection in a genome-wide association analysis.
    Ann Hum Genet. 2010 Sep 1;74(5):416-28 PMID: 20642809
  23. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.
    Am J Hum Genet. 2008 Nov;83(5):623-32 PMID: 18976728
  24. Common variants at 12q14 and 12q24 are associated with hippocampal volume.
    Nat Genet. 2012 Apr 15;44(5):545-51 PMID: 22504421
  25. The clinical use of structural MRI in Alzheimer disease.
    Nat Rev Neurol. 2010 Feb;6(2):67-77 PMID: 20139996
  26. Voxelwise gene-wide association study (vGeneWAS): multivariate gene-based association testing in 731 elderly subjects.
    Neuroimage. 2011 Jun 15;56(4):1875-91 PMID: 21497199
  27. TiGER: a database for tissue-specific gene expression and regulation.
    BMC Bioinformatics. 2008 Jun 09;9:271 PMID: 18541026
  28. Fast robust automated brain extraction.
    Hum Brain Mapp. 2002 Nov;17(3):143-55 PMID: 12391568
  29. Elastic-net regularization approaches for genome-wide association studies of rheumatoid arthritis.
    BMC Proc. 2009 Dec 15;3 Suppl 7:S25 PMID: 20018015
  30. Common Alzheimer's disease risk variant within the CLU gene affects white matter microstructure in young adults.
    J Neurosci. 2011 May 4;31(18):6764-70 PMID: 21543606
  31. Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.
    Alzheimers Dement. 2011 Jul;7(4):474-485.e4 PMID: 21784356
  32. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods.
    J Magn Reson Imaging. 2008 Apr;27(4):685-91 PMID: 18302232
  33. Multilocus genetic analysis of brain images.
    Front Genet. 2011 Oct 21;2:73 PMID: 22303368
  34. The Alzheimer's Disease Neuroimaging Initiative: Annual change in biomarkers and clinical outcomes.
    Alzheimers Dement. 2010 May;6(3):257-64 PMID: 20451874
  35. Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N=1198) using genome-wide search.
    Mol Psychiatry. 2011 Sep;16(9):927-37, 881 PMID: 21502949
  36. Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis.
    Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 5;150B(1):50-5 PMID: 18449908
  37. A tutorial on statistical methods for population association studies.
    Nat Rev Genet. 2006 Oct;7(10):781-91 PMID: 16983374
  38. Risk prediction using genome-wide association studies.
    Genet Epidemiol. 2010 Nov;34(7):643-52 PMID: 20842684
  39. Genome-wide analysis reveals novel genes influencing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease.
    Neuroimage. 2010 Jun;51(2):542-54 PMID: 20197096
  40. Voxelwise genome-wide association study (vGWAS).
    Neuroimage. 2010 Nov 15;53(3):1160-74 PMID: 20171287
  41. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space.
    J Comput Assist Tomogr. 1994 Mar-Apr;18(2):192-205 PMID: 8126267
  42. Pathway-based approaches to imaging genetics association studies: Wnt signaling, GSK3beta substrates and major depression.
    Neuroimage. 2010 Nov 15;53(3):908-17 PMID: 20219685
  43. Combining least absolute shrinkage and selection operator (LASSO) and principal-components analysis for detection of gene-gene interactions in genome-wide association studies.
    BMC Proc. 2009 Dec 15;3 Suppl 7:S62 PMID: 20018056
  44. Meeting the Challenges of Neuroimaging Genetics.
    Brain Imaging Behav. 2008 Dec 1;2(4):258-263 PMID: 20016769
  45. Improved optimization for the robust and accurate linear registration and motion correction of brain images.
    Neuroimage. 2002 Oct;17(2):825-41 PMID: 12377157
  46. A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM).
    Philos Trans R Soc Lond B Biol Sci. 2001 Aug 29;356(1412):1293-322 PMID: 11545704
  47. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.
    J Clin Psychiatry. 2007 Apr;68(4):613-8 PMID: 17474819
  48. The future of association studies: gene-based analysis and replication.
    Am J Hum Genet. 2004 Sep;75(3):353-62 PMID: 15272419
  49. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
    Neurology. 1984 Jul;34(7):939-44 PMID: 6610841
  50. A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.
    BMC Med Genomics. 2008 Sep 29;1:44 PMID: 18823527
  51. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain.
    Nat Genet. 2011 May 29;43(7):706-11 PMID: 21623373
  52. GeneNote: whole genome expression profiles in normal human tissues.
    C R Biol. 2003 Oct-Nov;326(10-11):1067-72 PMID: 14744114
  53. Efficient control of population structure in model organism association mapping.
    Genetics. 2008 Mar;178(3):1709-23 PMID: 18385116
  54. 3D characterization of brain atrophy in Alzheimer's disease and mild cognitive impairment using tensor-based morphometry.
    Neuroimage. 2008 May 15;41(1):19-34 PMID: 18378167
  55. A new role for endophenotypes in the GWAS era: functional characterization of risk variants.
    Harv Rev Psychiatry. 2010 Jan-Feb;18(1):67-74 PMID: 20047462
  56. A genome-wide scan for common alleles affecting risk for autism.
    Hum Mol Genet. 2010 Oct 15;19(20):4072-82 PMID: 20663923
  57. BDNF gene effects on brain circuitry replicated in 455 twins.
    Neuroimage. 2011 Mar 15;55(2):448-54 PMID: 21195196
  58. Mining gold dust under the genome wide significance level: a two-stage approach to analysis of GWAS.
    Genet Epidemiol. 2011 Feb;35(2):111-8 PMID: 21254218
  59. Interacting haplotypes at the NPAS3 locus alter risk of schizophrenia and bipolar disorder.
    Mol Psychiatry. 2009 Sep;14(9):874-84 PMID: 18317462
  60. Comparison of statistical approaches to rare variant analysis for quantitative traits.
    BMC Proc. 2011 Nov 29;5 Suppl 9:S113 PMID: 22373209
  61. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.
    Arch Neurol. 2008 Jan;65(1):45-53 PMID: 17998437
  62. Genome-wide gene and pathway analysis.
    Eur J Hum Genet. 2010 Sep;18(9):1045-53 PMID: 20442747
  63. Discovering genetic associations with high-dimensional neuroimaging phenotypes: A sparse reduced-rank regression approach.
    Neuroimage. 2010 Nov 15;53(3):1147-59 PMID: 20624472
  64. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.
    Nat Genet. 2007 Feb;39(2):168-77 PMID: 17220890
  65. The endophenotype concept in psychiatry: etymology and strategic intentions.
    Am J Psychiatry. 2003 Apr;160(4):636-45 PMID: 12668349
  66. Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease.
    PLoS One. 2009 Aug 07;4(8):e6501 PMID: 19668339
  67. Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism.
    Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):869-76 PMID: 17503474
  68. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.
    Hum Mol Genet. 2007 Apr 15;16(8):865-73 PMID: 17317784
  69. Enhanced signal detection in neuroimaging by means of regional control of the global false discovery rate.
    Neuroimage. 2007 Oct 15;38(1):43-56 PMID: 17825583
  70. Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.
    Stroke. 2010 Feb;41(2):210-7 PMID: 20044523
  71. Alzheimer's disease risk gene, GAB2, is associated with regional brain volume differences in 755 young healthy twins.
    Twin Res Hum Genet. 2012 Jun;15(3):286-95 PMID: 22856364
  72. The Clinical Dementia Rating (CDR): current version and scoring rules.
    Neurology. 1993 Nov;43(11):2412-4 PMID: 8232972
  73. Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA.
    Hum Brain Mapp. 2009 Jan;30(1):241-55 PMID: 18072279
  74. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
    Nat Genet. 2009 Oct;41(10):1094-9 PMID: 19734903
  75. Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans.
    Alzheimers Dement. 2010 May;6(3):265-73 PMID: 20451875
  76. Elucidating the genetic architecture of familial schizophrenia using rare copy number variant and linkage scans.
    Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16746-51 PMID: 19805367
  77. Accommodating linkage disequilibrium in genetic-association analyses via ridge regression.
    Am J Hum Genet. 2008 Feb;82(2):375-85 PMID: 18252218
  78. Identifying gene regulatory networks in schizophrenia.
    Neuroimage. 2010 Nov 15;53(3):839-47 PMID: 20600988
  79. Imaging genomics.
    Curr Opin Neurol. 2010 Aug;23(4):368-73 PMID: 20581684
  80. A classification of hand preference by association analysis.
    Br J Psychol. 1970 Aug;61(3):303-21 PMID: 5457503
Article Info
Journal
Frontiers in neuroscience
Abbr.
Front Neurosci
ISSN
1662-453X
DOI
10.3389/fnins.2012.00115
Published
2012-00-00
Epub
2012-00-06
Pages
115
Language
English
Region
Switzerland
NLM ID
101478481
PMCID
PMC3412288
Grants
NIA NIH HHS · R01 AG040060 · United States
NCRR NIH HHS · R21 RR019771 · United States
NIA NIH HHS · P50 AG016570 · United States
NICHD NIH HHS · R01 HD050735 · United States
NIA NIH HHS · K01 AG030514 · United States
NIBIB NIH HHS · R21 EB001561 · United States
NIA NIH HHS · F30 AG041681 · United States
NIGMS NIH HHS · T32 GM008042 · United States
NIA NIH HHS · U24 AG021886 · United States
NIA NIH HHS · U01 AG024904 · United States
NIA NIH HHS · U19 AG010483 · United States
NIMH NIH HHS · R01 MH097268 · United States
NIA NIH HHS · P30 AG010129 · United States
External Links
PubMed source DOI: 10.3389/fnins.2012.00115 PMC Full Text View journal details
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