Neurosurg Focus 28 (1):E2, 2010 Genome-wide association studies: a powerful tool for neurogenomics MATTHEW C. COWPERTHWAITE , PH.D.,1,2 DEEPANKAR MOHANTY ,3 AN D MARK G. BURNETT , M.D.1 1NeuroTexas Institute, St. David’s Medical Center; 2Center for Systems and Synthetic Biology; and 3Section of Neurobiology, The University of Texas at Austin, Texas As their power and utility increase, genome-wide association (GWA) studies are poised to become an im- portant element of the neurosurgeon’s toolkit for diagnosing and treating disease. In this paper, the authors review recent findings and discuss issues associated with gathering and analyzing GWA data for the study of neurologi- cal diseases and disorders, including those of neurosurgical importance. Their goal is to provide neurosurgeons and other clinicians with a better understanding of the practical and theoretical issues associated with this line of research. A modern GWA study involves testing hundreds of thousands of genetic markers across an entire ge- nome, often in thousands of individuals, for any significant association with a particular disease. The number of markers assayed in a study presents several practical and theoretical issues that must be considered when planning the study. Genome-wide association studies show great promise in our understanding of the genes underlying com- mon neurological diseases and disorders, as well as in leading to a new generation of genetic tests for clinicians. (DOI: 10.3171/2010.10.FOCUS09186) KEY WOR D S • neurogenomics • genetics • neurosurgery goal of molecular genetics is to discover the ge- date.52,53 In general, these studies have 1) reinforced the netic architecture of human phenotypes, espe- importance of the genetic variation that underlies pheno- cially diseases. The research community has re- typic variation, 2) illustrated that genetic variation almost Acently made great strides toward associating loci (genes) always results from multiple Mendelian mutations rather with phenotypes (diseases), but much work remains.80 than a single mutation, and 3) demonstrated that genetic These advances have resulted from significant increases in variation typically explains only a small fraction of the the scale and power of genetic-linkage tests, which have observed phenotypic variation.4,80,114 Within the field of grown from candidate-gene analyses to GWA studies. neuroscience, recent GWA studies have provided in- Genome-wide association studies are intended to ad- sights into the genetic basis of many common neurologi- dress some of the shortcomings of traditional candidate- cal diseases and disorders (Table 1). Such studies have gene linkage tests. Classic linkage studies are typically been conducted for conditions including Parkinson dis- difficult to conduct, at least in part because they require ease,39,67,93,113 malignant gliomas,23,95,109,143 multiple sclero- a priori knowledge about the biology of the disease under sis,7,29,90 Alzheimer disease,15,18,41,72,73 autism,3,8,22,45,75,107,133 study (to select candidate genes) as well as a familiarity schizophrenia,25,119,138 lumbar disc disease,131 idiopathic with the genetic variants (that is, mutations) in the candi- scoliosis,43,140 and restless-leg syndrome.36,139 date genes that could alter function or expression.113 Ad- Without doubt, the field of genomics is going to play ditionally, there is an inherent bias in the candidate-gene a central role in the clinical care of the future neurologi- approach stemming from the typically small number of cal patient. Physicians will therefore need to have at least genes that are selected for testing. The low-throughput a basic understanding of the research tools and concepts nature of candidate-gene studies obviously makes them routinely used in this field. The purpose of this review ill suited for testing roughly 30,000 genes and the mil- is to familiarize the clinician with the fundamentals of lions of observed genetic variants in the human genome. GWA studies and to highlight their potential clinical ap- There has been a significant increase in the number plication. of GWA studies being conducted, with ~ 400 published to Genome-Wide Association Models Abbreviations used in this paper: GWA = genome-wide associa- tion; HWE = Hardy-Weinberg equilibrium; SNP = single-nucleotide Recent progress toward understanding human ge- polymorphism. netic variation has advanced genetic-linkage and genet- Neurosurg Focus / Volume 28 / January 2010 1 Unauthenticated | Downloaded 09/24/21 06:12 PM UTC M. C. Cowperthwaite, D. Mohanty, and M. G. Burnett TABLE 1: Genome-wide association studies of common diseases ic-association studies from candidate-gene analyses to 98 and disorders of the brain, spine, and nervous system* GWA studies. The power of the GWA approach lies in the breadth and number of genetic variants tested during Condition Studied Reference the course of a study. The GWA study also has the advan- tage of being an unbiased search for the genetic variants neurooncology associated with a particular disease and therefore offers glioma 109 the possibility of discovering new associations of genes and pathways with diseases.4 high-grade glioma 143 neuroblastoma 77 Genome-Wide Association Theory high-risk neuroblastoma 24 A phenotype is an observable trait produced by an cerebrovascular disease underlying genotype. The genetic differences among in- dividuals in the human population are commonly called intracranial aneurysm 20 “mutations” and most frequently are single-nucleotide 11,80 hemorrhagic stroke 9 changes within the DNA sequences of genes. Many mutations are expected to be harmful and thus to be re- ischemic stroke 47, 79, 144 moved from the population by natural selection. Fewer neurological disease mutations are expected to be beneficial or fitness neutral, age-related macular 62 and such mutations can persist in a population over time degeneration while proceeding to fixation (every individual carries it) or loss (lost by the actions of selection and drift); with Alzheimer disease 2, 15, 18, 26, 41, 72, 73, 96, 103, either fate, any genetic variation is lost and therefore not 135, 136 observable. Prior to being fixed or lost, a mutation is car- amyotrophic lateral sclerosis 21, 27, 34, 35, 38, 63, 105, 129, 130 ried by only part of the population and is referred to as Creutzfeldt-Jakob susceptibility 81 a “polymorphism.” Single-nucleotide polymorphisms are commonly used as genetic markers in GWA studies and multiple sclerosis 6, 7, 12, 28, 29, 57, 59, 90 are the focus of this review—although alternative genetic Parkinson disease 42, 76, 93 features can be used for GWA studies. These alternatives progressive supranuclear palsy 82 may be particularly useful for GWA studies of psychiatric disorders, in which genetic features such as gene copy- restless legs syndrome 36, 104, 139 number variations14,45,107,119 and gross chromosomal rear- brain function & physiology rangements8 appear to be important to the genetic etiol- cognition 97, 108 ogy of this class of diseases. The aim of a typical GWA study is to associate one or memory 94 more SNPs with a particular disease phenotype (Fig. 1). pain 60 The tested SNPs are not expected to be the causal genetic factors; rather, they are used to mark (“tag”) particular brain vol 12 regions of chromosomes that likely contain many genetic sleep 46 variants in high linkage disequilibrium with the tested attention deficit hyperactivity 5, 64, 65, 68, 83, 87, 117 SNP. Linkage disequilibrium occurs when 2 or more al- disorder leles at distinct genetic loci occur together significantly more or less frequently than expected by chance based autism 75, 133 on the constituent allele frequencies. Single-nucleotide bipolar disorder 13, 40, 51, 106, 115, 116, 137, 145 polymorphisms are therefore an efficient way to screen major depressive disorder 85, 120 many mutations at once, and thus identify chromosomal locations within which the true causal variants are likely panic disorder 91 to reside. In fact, the true causal variant may not itself be neuroticism 111, 128 a nucleotide mutation—it may be an insertion or deletion mutation. schizophrenia 25, 58, 61, 66, 88, 89, 110, 112, 118, Genome-wide association studies differ in their as- 119, 121, 132, 138 sumptions about the type of genetic variation underlying personality dimensions 123 the disease of interest. Most such studies operate un- addiction der the “common disease/common variant” hypothesis, which proposes that phenotypic variation is the result of alcohol dependence 125 many common SNPs, each of which contributes only a methamphetamine 126 modest effect.100 An alternative hypothesis, the “multiple dependence rare variant” hypothesis, proposes that phenotypic varia- nicotine dependence 17, 19, 37, 124, 127 tion results from the potentially more modest effects of many rare SNPs.98 These two hypotheses are not neces- * Compiled from information contained in the National Human Genome sarily mutually exclusive—the variation underlying a Research Institute GWA study catalog.52,53 disease may fall into both categories; rather they are in- 2 Neurosurg Focus / Volume 28 / January 2010 Unauthenticated | Downloaded 09/24/21 06:12 PM UTC Genome-wide association guide for neurosurgeons Fig. 1. Schematic representation of a GWA study. Left: A mutation (black circles) entering and spreading through a popu- lation over time. Right: A contingency table in which the mutation is significantly more abundant among the cases than the controls. tended to guide the design,