The following are major areas of study and methodological approaches at the Institute for Behavioral Genetics:
- John K. Hewitt
- Thomas J. Crowley
- Michael C. Stallings
- Robin Corley
- Ken Krauter
- Susan Mikulich-Gilbertson
- Soo H. Rhee
- Gregory Carey
- Stacey Cherny
- Andrew Smolen
- Susan Young
- Marissa A. Ehringer
- Hopfer, C.J., Lessem, J.M., Hartman, C.A., Stallings, M.C., Cherny, S.S., Corley, R.P., Hewitt, J.K., Krauter, K.S., Mikulich-Gilbertson, S.K., Rhee, S.H., Smolen, A., Young, S.E., Crowley, T.J. (2006). A genome-wide scan for loci influencing adolescent cannabis dependence symptoms: Evidence for linkage on chromosomes 3 and 9. Drug and Alcohol Dependence, 89, 34-41. PUBMED abstract
- Ehringer, M.A., Rhee, S.H., Young, S.E., Corley, R.P., Hewitt, J.K. (2006). Genetic and environmental contributions to common psychopathologies of childhood and adolescence: A study of twins and their siblings. Journal of Abnormal Child Psychology, 34, 1-17. PUBMED abstract
- Stallings, M.C., Corley, R.P., Dennehey, B., Hewitt, J.K., Krauter, K.S., Lessem, J.M., Mikulich-Gilbertson, S.K., Rhee, S.H., Smolen, A., Young, S.E., & Crowley, T.J. (2005). A genome-wide search for quantitative trait loci influencing antisocial drug dependence in adolescence. Archives of General Psychiatry, 62, 1042-1051. PUBMED abstract
- Willcutt, E.G., Pennington, B.F., Duncan, L.E., Smith, S.S., Keenan, J.M., Wadsworth, S., DeFries, J.C., & Olson, R.K. (2010). Understanding the complex etiologies of developmental disorders: Behavioral and molecular genetic approaches. Journal of Developmental and Behavioral Pediatrics, 31(7), 533-544. PUBMED abstract
- Friend, A., DeFries, J.C., & Olson, R.K. (2008). Parental Education Moderates Genetic Influences on Reading Disability. Psychological Science,19, 1124-1130.>PUBMED abstract
- Christopher, M. E., Miyake, A., Keenan, J. M., Pennington, B. F., DeFries, J. C., Wadsworth, S. J., Willcutt, E. G., & Olson, R. K. (2012). Predicting word reading and comprehension with executive function and speed measures: A latent variable analysis. Journal of Experimental Psychology: General, 141(3), 470–488. PUBMED abstract
- Liao, C.-Y., Rikke, B.A., Johnson, T. E., Diaz, V. and Nelson, J.F., 2010 No evidence that competition for food underlies lifespan shortening by dietary restriction in multiply housed mice: Response to commentary. Aging Cell
- Liao, C.-Y., Rikke, B.A., Johnson, T. E., Diaz, V. and Nelson, J.F., 2009 Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9:92-95. PMCID 19878144.
Evolutionary genetics is a sub-branch of population genetics that studies (a) the evolutionary processes that account for changes in gene frequency over time and (b) the causes and consequences of existing genetic variation. Behavioral genetics is the study of genetic variation underlying human psychological traits. Evolutionary behavioral genetics combines these two fields. At IBG, we recognize the importance of taking an evolutionary perspective in understanding the genetic variation that underlies human disorders and other psychological traits. This approach is the flip side of the coin to the standard evolutionary psychology approach, which typically focuses on human universals and adaptations.
We are using whole genome SNP (single nucleotide polymorphism) data to understand the patterns of genetic variation, which in turn provides information on the roles of directional selection, balancing selection, mutation, and genetic drift on the genes that affect mental health traits. These studies overlap considerably with those using statistical genetics techniques, although we are open to using any method that can substantively increase knowledge in this area. We are also comparing human SNP data to SNP data from non-human primates to pinpoint genes that may underlie human-specific traits. In the future, sequencing data (data on every nucleotide in an individual's genome) will be available, which will dramatically expand our ability to answer fundamental questions about human genetic variation.
- SNP homozygosity study: Using SNP data, Keller and McQueen are assessing individuals' degree of homozygosity to understand the role of directional dominance and purifying selection on various mental health traits.
- Recent selection on genes underlying mental health: Keller and McQueen are scanning the genome to assess for areas that have been under recent positive selection, and noting which of these areas influence mental health traits.
- Evolutionary genomics of human cognition: To gain insights into the evolutionary genomics of human and great ape lineages, Sikela and colleagues are using cDNA aCGH to identify lineage-specific gene duplications or losses that have occurred between these lineages. Of particular interest are those human lineage-specific genes that underlie the cognitive abilities unique to the human brain, and how such genes, when defective, lead to cognitive disability.
- Genetics and genetic architecture of complex traits: Evans and Keller are exploring the genetic architecture of complex traits, including substance use and psychiatric disorders. Using a range of statistical genetic methods and datasets of up to 500,000 individuals with whole-genome and phenotype data, they are exploring the frequency, distribution, and functional annotation of variants that influence polygenic traits.
The Institute for Behavioral Genetics has both human and animal studies methodological approaches used by researchers. At the intersection of these broad classes of methodological approaches are the specific topics studied at IBG
Adams CA, Yonchek J, Schulz K, Graw S, Stitzel J, Teschke P, and Stevens K. 2012 Reduced Chrna7 expression in mice is associated with decreases in hippocampal markers of inhibitory function: implications for neuropsychiatric diseases. Neuroscience 207:274-82.
- Tammimäki A, Horton WJ, Stitzel JA. 2011. Recent advances in gene manipulation and nicotinic acetylcholine receptor biology. Biochem Pharmacol. 82:808-19
- Keller, M. C., Medland, S. E., & Duncan, L. E. (2010). Are extended twin family designs worth the trouble? A comparison of the bias, precision, and accuracy of parameters estimated in four twin family models. Behavior Genetics, 40, 377-393. [Fulker Award winner, bestpaper published in Behavioral Genetics, 2010].
- Keller, M. C., Medland, S. E., Duncan, L. E., Hatemi, P. K., Neale, M. C., Maes, H. H. M., Eaves, L. J. (2009). Modeling extended twin family data I: Description of the Cascade model. Twin Research and Human Genetics, 29, 8-18.
Brain imaging is used to investigate the neural substrates of cognitive control and decision making in various studies at IBG. With the arrival of a new 3T scanner in Boulder, several studies are underway to examine neural substrates of individual differences in executive functions in the CTS and LTS twin samples. The data will be used in both biometric twin studies and molecular genetic studies to examine brain correlates of the genetic variance in these phenotypes.
The following faculty specialize in fMRI Research:
- Papke RL, Wecker L and Stitzel JA. 2010. Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther. 333:501-518
- McClure-Begley TD, King NM, Collins AC, Stitzel JA, Wehner JM, Butt CM. 2009. Acetylcholine-Stimulated [3H]GABA Release from Mouse Brain Synaptosomes is Modulated by α4β2 and α4α5β2 Nicotinic Receptor Subtypes. J. Neurochem. 75:918-26
- Mexal S, Horton, WJ, Crouch EL, Maier SIB, Wilkinson AL, Marsolek M, and Stitzel JA. 2012. Diurnal variation in nicotine sensitivity in mice: role of genetic background and melatonin. Neuropharmacology 63:966-73
- Wilking JA, Nguyen V, Hesterberg K, Cyboron A, Hua A, Stitzel JA. 2012. Age and strain effects on oral nicotine consumption and baseline anxiety. Behav. Brain Res. 233:280-7
- Wilking JA, Hesterberg K, Crouch EL, Homanics G, and Stitzel JA. 2010. Chrna4 T529A knockin mice exhibit altered sensitivity to nicotine. Pharmacogenetics and Genomics 20:121–130
The methodological approaches of genetic epidemiology and statistical genetics are primarily focused on the identification of genetic variation underlying complex disease. Here at IBG, there is a particular interest in the genetics of psychiatric, behavioral and neurologic disorders. IBG researchers make use of well-characterized longitudinal data arising from both family-based and population-based samples. Statistical and epidemiological approaches being used at IBG include linkage analysis, genome-wide association, candidate gene association and the analysis of sequence data.
All human studies utilize statistical genetics. IBG uses data from the following studies, and others:
- UK Biobank
- Psychiatric Genomics Consortium (PGC)
- Adolescent Brain Cognitive Development study (ABCD)
The following faculty specialize in Statistical Genetics Research:
- Evans, LM, R Tahmasbi, SI Vrieze, G Abecasis, S Das, D Bjelland, T DeCandia, Haplotype Reference Consortium, ME Goddard, BM Neale, J Yang, PM Visscher, MC Keller. 2018 Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits. Nature Genetics. 50:737-745. DOI: 10.1038/s41588-018-0108-x. PMC5934350
- Evans, LM, R Tahmasbi, SI Vrieze, G Abecasis, S Das, D Bjelland, T DeCandia, Haplotype Reference Consortium, ME Goddard, J Yang, PM Visscher, MC Keller. In press. IBD haplotypes can account for the missing heritability of complex traits in homogeneous samples. Heredity. DOI:10.1038/s41437-018-0067-0
- Evans, LM, MC Keller. 2018. Correspondence: Using partitioned heritability methods to explore genetic architecture. Nature Reviews Genetics. DOI:10.1038/nrg.2018.6
- Johnson, EC, LM Evans, MC Keller. 2018 Relationship between estimated autozygosity and complex traits in the UK Biobank. PLoS Genetics. 14(7):e1007556. DOI:10.1371/journal.pgen.1007556.
- Stallings M.C., Corley R.P., Dennehey B., Hewitt J.K., Krauter K.S., Lessem J.M., Mikulich-Gilbertson S.K., Rhee S.H., Smolen A., Young S.E., & Crowley T.J. (2005). A genome-wide search for quantitative trait Loci that influence antisocial drug dependence in adolescence. Archives of General Psychiatry, 62, 1042-1051. | pubmed abstract |
- McQueen MB, Devlin B, Faraone SV, Nimgaonkar VL, Sklar P, Smoller JW, Abou Jamra R, Albus M, Bacanu SA, Baron M, Barrett TB, Berrettini W, Blacker D, Byerley W, Cichon S, Coryell W, Craddock N, Daly MJ, Depaulo JR, Edenberg HJ, Foroud T, Gill M, Gilliam TC, Hamshere M, Jones I, Jones L, Juo SH, Kelsoe JR, Lambert D, Lange C, Lerer B, Liu J, Maier W, Mackinnon JD, McInnis MG, McMahon FJ, Murphy DL, Nothen MM, Nurnberger JI, Pato CN, Pato MT, Potash JB, Propping P, Pulver AE, Rice JP, Rietschel M, Scheftner W, Schumacher J, Segurado R, Van Steen K, Xie W, Zandi PP, Laird NM. (2005). Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. American Journal of Human Genetics, 77, 582-595. | pubmed abstract |
- Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB, Colditz G, Hinney A, Hebebrand J, Koberwitz K, Zhu X, Cooper R, Ardlie K, Lyon H, Hirschhorn JN, Laird NM, Lenburg ME, Lange C, Christman MF. (2006). A common genetic variant is associated with adult and childhood obesity. Science, 312, 279-283. | pubmed abstract |
- Keller, M. C., Simonson, M. A., Ripke, S., Neale, B. M., Gejman, P.V., Howrigan, D. P., Lee, S. H., Lencz, T., Levinson, D. F., Sullivan, P. F., & the Schizophrenia Psychiatric Genome- Wide Association Study (GWAS) Consortium (2012). Runs of homozygosity implicate autozygosity as a schizophrenia risk factor. PLoS Genetics, 8, e1002656.
- Lee, S. H., DeCandia, T., Ripke, S., Yang, J., The Schizophrenia Psychiatric Gemone-Wide Association Study Consortium (PGC-SZ), The International Schizophrenia Consortium (ISC), The Molecular Genetics of Schizophrenia Collaboration (MGS), Sullivan, P. F., Goddard, M. E., Keller, M. C.†, Visscher, P. M. †, Wray, N. R. † (2012). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genetics, 44, 247-250. (†joint senior author)
- The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS)Consortium (2011). Genome-wide association study identifies five novel schizophrenia loci. Nature Genetics, 43, 969-976.
- Simonson, M. A., Wills, A. G., Keller, M. C. †, & McQueen, M. B. † (2011). A comprehensive approach assessing the contribution of polygenic variation to risk of cardiovascular disease, BMC Medical Genetics, 12, 146. (†joint senior author)
- Howrigan, D. P, Simonson, M. A, & Keller, M. C. (2011). Detecting autozygosity using runs of homozygosity: A comparison of three autozygosity detection algorithms. BMC Genomics, 12, 460-475.
- Keller, M. C., Visscher, P. M., & Goddard, M. E. (2011). Quantification of inbreeding due to distant ancestors and its detection using dense SNP data. Genetics, 189, 237-249
- Duncan, L. E. & Keller, M. C. (2011). A critical review of the first ten years of candidate gene-by-environment interaction research in psychiatry. American Journal of Psychiatry, 168, 1041-1049.