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KEY POINTS * Either population-based or family-based designs can be used in gene-association studies. Population-based designs use unrelated individuals; family-based designs use probands

and their relatives, typically either parents or siblings. * Genetic-association studies face the obstacles of population substructures and multiple testing. * Family-based designs are

favoured because they are robust against confounding due to population substructures and test both linkage and association. * Case–control designs are preferred for the relative ease of data

collection. They have modest power advantages, depending on the prevalence of the disease. * Family-based designs can be extended to incorporate pedigrees and complex phenotypes. *

Screening tools are available for family-based designs that allow the multiple-testing problem, which is an important issue in whole-genome association studies, to be handled. ABSTRACT Both

population-based and family-based designs are commonly used in genetic association studies to locate genes that underlie complex diseases. The simplest version of the family-based design —

the transmission disequilibrium test — is well known, but the numerous extensions that broaden its scope and power are less widely appreciated. Family-based designs have unique advantages

over population-based designs, as they are robust against population admixture and stratification, allow both linkage and association to be tested for and offer a solution to the problem of

model building. Furthermore, the fact that family-based designs contain both within- and between-family information has substantial benefits in terms of multiple-hypothesis testing,

especially in the context of whole-genome association studies. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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ROBUSTNESS Article Open access 10 March 2025 GENOME-WIDE ASSOCIATION STUDIES Article 26 August 2021 AN ENHANCED FRAMEWORK FOR LOCAL GENETIC CORRELATION ANALYSIS Article 10 March 2025

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designs. _Am. J. Epidemiol._ 149, 693–705 (1999). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the National Institute of Mental

Health and the National Heart, Lung and Blood Institute, USA. We would like to thank C. Garcia for with help with the preparation of this manuscript. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Biostatistics, Harvard School of Public Health, Boston, 02115, Massachusetts, USA Nan M. Laird & Christoph Lange Authors * Nan M. Laird View author

publications You can also search for this author inPubMed Google Scholar * Christoph Lange View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING

AUTHOR Correspondence to Nan M. Laird. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED LINKS RELATED LINKS FURTHER INFORMATION FBAT

homepage Framingham Heart Study Human Genome Project Nan Laird's homepage PBAT homepage GLOSSARY * Linkage analysis A method for localizing genes that is based on the co-inheritance of

genetic markers and phenotypes in families over several generations. * Association studies A gene-discovery strategy that compares allele frequencies in cases and controls to assess the

contribution of genetic variants to phenotypes in specific populations. * Candidate gene A gene for which there is evidence, usually functional, for a possible role in a disease or trait of

interest. * Power The ability of a study to obtain a significant result if this result is true in the underlying population from which the study subjects were sampled. * Multiple-hypothesis

testing Many different statistical tests are used on the same sample; for example, many genetic markers might be tested against many different phenotypes. Failure to account for multiple

testing inflates the study-wide type-1 error rate. * Population substructure Characteristics of a population, such as admixture, population stratification and/or inbreeding, which might

distort the distribution of the standard association statistics, leading to increased type-1 error and/or decreased power. * Genome-wide association studies Studies designed to look for

association between disease and a dense set of markers covering the entire genome. * Case–control study An epidemiological study design in which cases with a defined condition and controls

without this condition are sampled from the same population. Risk-factor information is compared between the two groups to investigate the potential role of these in the aetiology of the

condition. * Case–cohort study Similar to a case–control study, except both cases and controls are drawn from an existing cohort of subjects who are being followed to study a broad spectrum

of diseases and risk factors. * Proband In a family study, this is the individual who is first identified in the family as having the disease under study. * Odds ratio The odds of exposure

to the susceptible genetic variant in cases compared with controls. If the odds ratio is significantly greater than one, then the genetic variant is associated with the disease. * Monte

Carlo A method for obtaining a _p_-value for a test statistic by drawing repeated samples from the null distribution of the data, computing the _p_-value for the same statistic for each

sample, and comparing the observed _p_-value to the distribution of _p_-values obtained from the samples. * Likelihood A statistical model for analysing data that requires specifying a

particular form for the distribution of the data. * Admixture This occurs when two or more subpopulations inbreed, so that two randomly chosen individuals in the population might have

different degrees of genetic heritage from the original subpopulations. * Population stratification The presence in a population of distinct strata or groups that show limited inbreeding;

they might have different disease rates and distinct allele-frequency distributions. Failure to control for the stratification can invalidate tests of association. * Linkage disequilibrium

(LD). This occurs when alleles at two different loci are associated in a population because of tight linkage. * Haplotype A set of alleles at different loci that are present together on the

same chromosome. * Phase The arrangement of alleles at multiple loci on homologous chromosomes. For example, in a diploid individual with genotype _Aa_ at one locus and genotype _Bb_ at

another locus, possible linkage phases are _BA/ba_ or _Ba/bA_, where '/' separates the two homologous chromosomes. * Covariance A measure of association between two variables that

characterizes the tendency for the two variables to co-vary around their mean in a systematic way. * Informative families Families that make a contribution to the FBAT test; that is, those

with at least one heterozygote parent, or sibships with at least two distinct genotypes. * Nuisance parameters Parameters that are not the primary focus of a statistical analysis, but for

which misspecficiation might lead to biased results, for example, allele frequency in association tests. * Sufficient statistics A data reduction function that retains all information about

an unknown parameter; they are used to remove the dependence of a test on nuisance parameters that are unknown or difficult to model. * Confounding A measure of the association between a

disease and a risk factor is distorted because other variables, associated with both the disease and the risk factor, are not controlled for in the calculation of the measure of association.

* Likelihood-ratio tests A class of statistical tests obtained by comparing the likelihood statistic under the alternative hypothesis to the likelihood under the null hypothesis. * Score

tests A class of statistical tests that are derived from a likelihood model and are generally easier to compute than likelihood-ratio tests. * Identity-by-descent (IBD). An allele shared by

two related individuals is said to be identical-by-descent if the allele is inherited from the same common ancestor. * Permutation An approach in which the actual data are randomized many

times to generate a distribution of outcomes, so that the fraction of observations with values that are more extreme than the outcome that is observed with the real data reflects the

statistical significance. * Outcome space Set of all possible genotype configurations for a specific pedigree that are plausible under Mendelian transmissions, and consistent with the

sufficient statistics for parental genotype. * Discordant sibs A family design for testing association that uses a case and his/her unaffected sib. * Nested models A sequence of statistical

models, each specifying a different hypothesis, such that each model in the sequence contains one more factor than the preceeding model. Nested models are often used to test for the presence

of interactions between two or more risk factors. * Multiplicative genetic model A genetic model for penetrance functions that assumes the relative risk for disease given two alleles is the

square of the relative risk for disease given only one allele. * Linear regression A statistical method used to test and to describe the linear relationship between two or more variables. *

Type-1 error The probability that the null hypothesis is falsely rejected. * Intermediate phenotypes or endophenotypes Measured biological variables intermediate between genotype and

external phenotype that can indicate susceptibility to, or manifest as early signs of, a wide range of diseases or disorders. * Imputed A statistical method for handling missing data which

replaces the missing values by estimated values. * Bonferroni or Hochberg corrections Statistical methods, proposed by Bonferroni and Hochberg, for controlling type-1 error (false positives)

in the presence of multiple testing. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Laird, N., Lange, C. Family-based designs in the age of large-scale

gene-association studies. _Nat Rev Genet_ 7, 385–394 (2006). https://doi.org/10.1038/nrg1839 Download citation * Issue Date: 01 May 2006 * DOI: https://doi.org/10.1038/nrg1839 SHARE THIS

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