Publications of Joseph D. Terwilliger, Ph.D.

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Review papers about concepts in complex disease gene mapping

• Terwilliger and Lee(2006)
  • This book chapter written for a textbook about anthropological genetics compares the study designs used in experimental genetics with those used in observational genetics, and by extension compares approaches used in observational genetics with those used in observational epidemiology, to demonstrate why epidemiological study designs are fundamentally inappropriate for study of the genetic portion of the etiology of complex traits. Rather emphasis is on methods for identification of, and work with unusual populations which represent some sort of naturally- occurring populations which mimic the sort of experiments we would like to design in a more malleable species. Further focus on the negative consequences of the recent focus on high-throughput engineering approaches in human genetics are discussed in this context as genetics moves from a field of science to a thought-free exercise in futile engineering at high expense for low return.
• Terwilliger and Weiss(2003)
  • This review paper in Annals of Medicine provides an overview and contrast of gene mapping methods with the techniques used in traditional environmental epidemiology to highlight the myriad reasons why gene mapping with population cohorts will not be a powerful approach for identification of novel genes related to some phenotype of interest. The purpose of this paper is largely to contrast epidemiology and genetics and to suggest that the most optimal way for these fields to work together would be for epidemiologists to measure phenotypes and environmental exposures as they do, only to do so on samples ascertained for purposes of gene mapping (i.e. from extremely nonrandom sampling of large pedigrees instead of random sampling of unrelated individuals.
• Terwilliger (2004)
  • This editorial written for the Korean journal "Genomics and Informatics" attempts to explain the differences between engineering and science, and their applications in the search for genes underlying complex human phenotypes. The sequencing and genotyping technologies, along with the advances in computer science and bioinformatics are examples of how engineering approaches are used in biology, but it is clear that this does not constitute scientific investigation, as it is mere application of technology, rather than hypothesis-driven research to ask questions. Clearly there is a role for engineering, but it has been made far too central to the current efforts to map genes by throwing good technology and poorly designed experiments, which is certainly inefficient, and likely to fail. The purpose of this editorial was to encourage more scientific approaches in gene mapping, rather than believing that technology will solve all our problems in the end...
• Terwilliger et sl (2002)
  • This critical review paper looks critically at issues of bias which lead to systematic overestimation of the amount of LD among sets of linked markers, overestimation of the effect size of any newly-identified locus, and so forth, against a background highlighting the lack of scientific substance behind the arguments in favor of the proposed haplotype map (HapMap) project. The overly politicized nature of the rhetoric in this field is highlighted as a warning to those thinking about jumping into this field of research without taking time to carefully and critically evaluate the prognosis for success from first principles...
• Terwilliger et al (2002)
  • This paper provides a conceptual overview of the various study designs used in genetic epidemiology and in gene mapping experiments, with a discussion of their strengths and limitations, emphasizing the truth that in humans we cannot do experiments, but must rather look for natural experiments that can inform about trait etiologies. An example, focusing on the populations of the Korean diaspora is discussed as an illustration of some of the strengths and limitations of each traditional design. Do not be distracted by the Chinese language abstract - the paper IS in English :)
• Terwilliger (2001)
  • This paper provides a mathematical description of linkage and linkage disequilibrium mapping in the presence of complete and error-free information on identity-by-descent relationships in populations, highlighting the extreme variation in LD patterns one expects across the genome, consistent with what is seen in real data. Further discussion of the relative advantages of collecting large multiplex families over unrelated individuals for association studies is presented, with mathematical explanations for why case-control studies are about the least powerful design possible for association analysis - second in futility only to parent-child trio designs in their lack of information
• Terwilliger and Goring(2000)
  • The first half of this paper provides an overview of basic concepts in statistical genetics and gene mapping, written for an audience of biological anthropologists unfamiliar with linkage and LD mapping concepts. The second half of the paper discusses real data from simple and complex traits, and a discussion of study design implications.
• Weiss and Terwilliger (2000)
  • This commentary discusses the statistical implications of the nondeterministic nature of genotype-phenotype relationships in complex traits on gene mapping experiments, with a discussion of the implications of technological advancements on our prognosis for unraveling the etiology of complex traits. The main point is that while technology is great, it is the real world biological truths that are making it difficult to understand trait etiology. This review discusses the implications of these truths...
• Terwilliger and Weiss (1998)
  • This review paper gives an overview of a myriad of reasons why linkage disequilibrium mapping is more fantasy than reality, as it works well on simplified mathematical models of reality that have no relationship to what the true state of nature really is. Most hype about LD mapping and haplotype maps comes from unrealistic models based on small samples, with a complete absence of any empirical or theoretcial evidence that it will work. Details described in this paper remain as legitimate today as in 1998, as no theoretical or empirical evidence has been presented in the intervening years to dispute any of the objections raised herein...
• Terwilliger (1998)
  • This is a mathematical discussion of the principles of linkage analysis from the Encyclopedia of Biostatistics, written for an audience of mathematicians with no prior knowledge of genetics.
• Terwilliger et al (1998)
  • This is not formally a review paper, but the main discussion of this paper is, in fact, a conceptual overview of linkage disequilibrium, the forces that create and destroy it, and a demonstration of symmetry between the dynamics of LD in diploid populations and the dynamics of traditional population genetics in haploid organisms!
• Terwilliger (1997)
  • This is a book review of Ken Weiss' classic book "Genetic variation and human disease: principles and evolutionary approaches". Ken Weiss' book is a must-read for anyone interested in complex traits, as he provides empirical and theoretical arguments about the likely spectrum of genetic risk factors in such traits, and their likely effect sizes, based on animal models, human disease data, and fundamental concepts of population genetics. It makes sense to listen to arguments presented by biological anthropologists in this context rather than genetic epidemiologists with little training in evolution, especially when the latter are the ones speaking the loudest in favor of association-based epidemiology studies...

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Research of theoretical importance hidden in data papers

• Varilo et al (2003)
  • Methods for correcting small-sample bias in estimates of the linkage disequilibrium parameter D-prime
• Lupu et al (2001)
  • Likelihood-based growth curve estimation
• Paunio et al (2001)
  • In this paper, the problem of maximizing the statistical evidence for linkage over many different analysis methods and disease models, multiple subdivisions of a larger dataset, and multiple diagnostic schemes, in the context of a genome-wide scan is addressed by a combination of genome-wide simulations assuming no linkage to anywhere in the genome, bootstrapping the replicates of each chromosome, and estimating the equivalent number of independent tests by curve fitting of the resulting maximized over models statistic to the distribution of the first order statistic from a series of N chi-square distributions, where the estimate of N would give an equivalent number of independent tests from the large number of correlated analyses performed in a study.
• Varilo et al (2000)
  • In this paper we developed a randomization test procedure to compare LD among two different populations where we had different sample sizes from the two groups. Clearly the power to detect LD is a function of the strength of the LD, as well as the sample size, so we did a repeated subsampling analysis to normalize the sample sizes from the two populations, compute a likelihood ratio statistic, and estimated its p-value by randomization.
• Hovatta et al (1999)
  • In this paper, a case-control study was performed in an extreme population isolate. Because the trait is familially correlated, when working in a small finite population, ascertaining cases will be equivalent to ascertaining distant relatives, more closely related to one another than a randomly ascertained set of controls. Using a method that is an early analog of the recently popular genomic-control approaches, we randomized case and control phenotypes and kept the LD relationships among the marker loci constant to estimate the expected number of positive findings in the genome scan, and found that we observed about twice as many positive findings in our study (at every significance level considered) than in a randomized genome scan, proving that there were differences between cases and controls at random markers... The proposed correction was to alter the null hypothesis to be "a little bit of LD" rather than "no LD", as described in Terwilliger and Weiss (1998).
• Hovatta et al (1998)
  • In this paper, I did a simulation study to examine the distance between the true location of a gene, and the position in the genome which gave the maximum lod score in a genome scan using affected-sib-pair analysis, conditional on that maximum occurring within 50cM of the true gene. It shows that even with sample sizes of as much as 1000 sibpairs, you could be easily as far as 10cM away from the true location of the gene, even if your maximum lod score is exceeding 3... This "hidden result" was put in an obscure "Molecular Psychiatry" paper, largely because I never thought it worthy of an entire paper of its own, being such an obvious and simple result, and because at least in this context it was important to get it published so I could refer to it when people say such ridiculous things as that because they have two linkage peaks 10cM apart they must be looking at two genes, rather than one, without any further evidence than this... Could be pure statistical fluctuation as we explain and describe in this paper.
• Lichtermann et al (1998)
  • In this paper we present a likelihood-based analysis approach to looking at "same-sex concordance" which had been hypothesized to be present in schizophrenia families. However, all previous studies had not conditioned their analysis on the fact that there is differential prevalence in males and females. In this paper, I performed a global analysis of all extant datasets for schizophrenia to demonstrate the lack of any significant evidence of excessive same-sex concordance in any of the earlier studies claiming it, as well as in all datasets pooled together... Further, we demonstrated that the power to detect any deviation from independence was extremely high in the available sample size...
• Hovatta et al (1997)
  • In this paper we demonstrated the ridiculous nature of the often-used parameter lambda-s in genetic epidemiology. We proved that this parameter cannot be estimated when you have complete ascertainment of an entire population of families, for once and for all showing the inutility of it for making inferences in genetic epidemiology. We provide a full likelihood based analysis of familial concordance of schizophrenia in Finnish nuclear pedigrees, within a given time-age range, subject to the contraints of our sampling frame, and developed a set of methods of broader applicability in such genetic epi studies, in the presence of complete ascertainment, as one often has in the Nordic countries, for example.
• Trembath et al (1997)
  • This paper presents an earlier version of the pseudomarker algorithm for joint linkage and LD analysis. While primitive at best, this algorithm has been more recently applied in variance components types of analysis for "joint" linkage and LD analysis, notably in SOLAR and other software packages. Note that in the paper, numerous numerical notation problems are present - for example,when something is written as L-BS(...), the minus sign was supposed to be SUBSCRIPT!!! Such problems make this difficult to read the methods section of, alas...
• Satsangi et al (1996) and Kuokkanen et al (1996)
  • These two papers coming out about the same time, both in Nature Genetics, provide the first presentation of the pseudomarker algorithm for nuclear pedigrees. By extending the equivalence of the ASP mean test to recessive linkage analysis to families with more than 2 sibs, a statistic that is always more powerful and better behaved than the traditional mean test was developed, and implemented in the SIBPAIR program, which is part of my ANALYZE program package.

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Statistical Methods Papers

• Terwilliger and Hiekkalinna (2006)
  • This paper demonstrates a further structural flaw in the argument for genome-wide association studies based on samples of unrelated individuals sharing some disease phenotype. Aside from the well-known objections based on etiological complexity, allelic heterogeneity, and various structural objections to the common variant/common disease dogma, this paper demonstrates the dangers of extrapolation from over-simplistic theoretical models. We demonstrate numerically that the oft-touted relationship between r-square linkage disequilibrium and sample size requirements in genome-wide association studies is fundamentally flawed and invalid in any but the most simplistic etiological models, most of which are not believed plausible by even the most ardent "true believers" in the CVCG theological dogma. We demonstrate simple examples in which one could have high power to detect a functional variant with reasonable sample size, were it genotyped, while a marker with r-squared LD of 0.8 would have no difference in distribution between cases and controls. While a simplistic example is demonstrated involving genetic heterogeneity, it is completely trivial to provide examples with the same property for which there are NO additional genetic risk factors whatsoever. Simply put, the theoretical basis for the HapMap is completely wrong if there is any risk factor influencing the disease other than a single common variant - and nobody in the world believes this is a plausible model for the allelic architecture of complex traits. If such a model held, family studies would be trivial to do, and substantially more powerful, as well!
• Hiekkalinna et al (2005)
  • This paper presents an overview of the AUTOGSCAN programs for automated genome scan analysis. For further information and to download software, please see http://www.helsinki.fi/~tsjuntun/autogscan/
• Goring et al (2001)
  • This paper illustrates the well-known fact that you cannot estimate the effect size of any locus in the same sample in which you initially identified the locus as being correlated to the trait. An often-overlooked truth, which explains much of the disappointments people have with replication studies, and why they grossly overestimate the importance of new mapping results routinely...
• Terwilliger (2000)
  • In this paper, I demonstrated that an extension of traditional heterogeneity analysis methods in linkage analysis can extract essentially all of the available information in the data under epistatic models, which is a natural extension of the fact that the A-test of locus heterogeneity is the most extreme form of gene-gene interaction possible... This paper gives a formal argument for why there is no power to identify epistasis, and why development of statistical methods designed to look at multiple disease loci simultaneously will not be more powerful than marginal analyses, at least for the qualitative trait case.
• Goring and Terwilliger (2000a)
  • In this paper, the effects of model errors on parametric lod scores are described conceptually. It is well-known that parametric two-point lod score tests are very robust to errors in the disease mode of inheritance assumptions. In this paper we present a device for extending this robustness to the multipoint analysis situation through the use of an "error" parameter, incorporated in the estimated "recombination fraction" in traditional two-point analysis. Errata from this paper (figures misordered!!) are described here.
• Goring and Terwilliger (2000b)
  • In this paper, the effects of genotyping errors at marker loci in linkage analysis are described formally. It is shown that these effects are symmetric with the effects of errors in the analysis model. Furthermore, a crude means of estimating genotyping errors genome-wide is presented, based on the distribution of observed lod scores in a genome scan. As a simple example, you should have roughly 50% of the genome showing a lod score of 0, and 50% showing lod scores greater than 0. If more than 50% of the genome shows a lod of 0 in sibpair analysis, or traditional linkage analysis, then you have reason to believe there is a high rate of genotyping errors. Similarly if you have no lod scores over 1, for example, this also tells you there are enormous genotyping error rates, as you expect a certain number of these by chance without a gene! Errata from this paper are likewise described here.
• Goring and Terwilliger (2000c)
  • This paper presents a conceptual overview of likelihood based linkage and LD analysis, emphasizing the effects of errors in the assumption one makes about the marker order, intermarker recombination fractions, marker locus allele frequencies (the effects of which are dramatically worse in multipoint than two-point analysis!), and marker-marker LD (which, if present but ignored in the analysis can have major effects on increasing false positive rates in linkage studies - a severe warning to all those doing studies of multiple tightly linked SNPs with linkage analysis programs based on assumptions of no LD - as is the case for most popular methods in use today...). It is shown that these parameters can all be treated as nuisance parameters in the analysis, however, to recover the appropriate false positive rates, at a large cost, however, in computational time...
• Goring and Terwilliger (2000d)
  • The most important paper of the bunch - in this paper we prove the algebraic equivalence between parametric analysis under a VERY wrong model to each of the following statistics - TDT, HRR, Case-control association test, Affected Sibpair tests, Affected Relative-pair tests, etc... Furthermore, we describe a method, PSEUDOMARKER, for joint analysis of all data structures, from singletons, to parent-child trios, to sibpairs, to large pedigrees, looking at linkage and LD jointly. This test is shown to be always more powerful than the conventional approaches, and has been automated in easy to use computer software, PSEUDOMARKER
• Terwilliger et al (1997)
  • In this paper, we proved that lod score peaks around true genes are on average twice as long as those which are false positives. Because of extensive debate in the literature about this topic, we performed a full theoretical analysis and simulation study to prove this for once and for all. Of course, the distribution of peak length is such that roughly 25% of false peaks would be longer than any true peak, making this of limited inferential value, but provided a complete refutation of one of the many extreme claims in the oft-cited Lander and Kruglyak(1995) paper which aimed to provide "rules" for linkage papers...
• Terwilliger (1995)
  • This paper presents a likelihood based method for analysis of linkage disequilibrium between a dichotomous trait-predisposing locus and one or many polymorphic marker loci. This method has been used hundreds of times in fine mapping of genes responsible for simple Mendelian traits. Errata are described here
• Terwilliger and Ott (1993)
  • This paper described the POLYLOCUS method for linkage analysis with multiple markers. Essentially, if a marker is uninformative in a given family (or meiosis), one simply looks at the next nearest informative marker as if they were at the same position. ALternative methods correcting for the intermarker distance have been applied as well (so-called multipoint polylocus analysis). These methods have been used frequently when multipoint analysis is computationally infeasible, and by extension of the argument in Goring and Terwilliger (2000a) these are more robust to model errors than traditional multipoint analysis anyway!
• Terwilliger, Speer, and Ott (1993)
  • In this paper a method for rapid simulation of entire chromosomes of linked markers is described, which can be done in the presence of various interference models, using any count-location process or renewal process model for recombination.
• Terwilliger, Ding, and Ott (1992)
  • In this paper from 1992, we present arguments why a genome-spanning map of SNPs may be more powerful than a less dense map of microsatellites, with caveats presented about informativeness of markers, lack of phase information, and inability to detect genotyping errors as well. To my everlasting shame, I advocated at this time that perhaps such a dense map of uninformative markers would be better than microsats and VNTRs which were then in vogue... A follow-up paper was submitted the next year (1993) explaining all the reasons why such a map of uninformative markers was probably not so useful after all, when genotyping errors, lack of phase information and other complications were incorporated in the analysis - but this paper was rejected with the argument being that "Now we have VNTRs and microsatellites - noone would ever consider going back to using uninformative markers like the old RFLPs ever again" I never followed up on this, but in retrospect wish I had. The reviewer comment above is quite amusing given the mad rush to find uninformative markers 10 years later...
• Terwilliger and Ott (1992a)
  • In this paper, we present a statistic which is algebraically equivalent to the TDT statistic, a year before Spielman and Ewens' infamous paper. In this manuscript, however, we proved that the TDT was NEVER the most powerful test of LD, largely because it throws away information from homozygous parents, which does have information about LD in it. Anyway, I never advocate using the TDT or the HRR statistics today, as it is much wiser to collect larger families, even for association analysis, and do a full pseudomarker analysis of linkage and LD jointly...
• Terwilliger and Ott (1992b)
  • In this paper we proposed a multisample bootstrap approach to correcting for maximizing the lod score over many different models. A much more refined version of this has been described and employed in Paunio et al (2001)

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Applications of PSEUDOMARKER

• Anttila et al (2006)
  • This paper used PSEUDOMARKER for joint linkage and LD analysis on a mixture of family structures with migraine
• Enattah et al (2002)
  • This paper used the PSEUDOMARKER program for joint linkage and LD analysis on a mixture of large multiplex families and singleton cases and controls to test for LD conditional on linkage to a variant involved in adult-type hypolactasia. Most significant thing in this paper, however, is that the variant which seems to be completely correlated with the trait is in an intron of a gene several kb away from the gene whose expression it is regulating... Scary news for those who still believe candidate genes and focus on cSNPs is a logical approach... Looks like it may not be after all ;)
• Liu et al (2002)
  • This paper used a pseudomarker linkage analysis method in a genome scan looking for Celiac disease genes
• Liu et al (2001)
  • This paper used a pseudomarker linkage analysis method in a search for bipolar genes
• Paavola et al (2001)
  • This paper used a pseudomarker linkage analysis method in a search for Inflammatory Bowel Disease genes
• Paunio et al (2001)
  • This paper used a pseudomarker linkage analysis method in a search for schizophrenia genes
• Magnusson et al (2000)
  • This paper used a pseudomarker linkage analysis method in a search for SLE genes
• Aita et al (1999)
  • This paper used a pseudomarker polylocus linkage analysis in a search for bipolar genes.
• Kainulainen et al (1999)
  • In this paper, an application of joint linkage and LD analysis with PSEUDOMARKER is presented. In this application, the analysis was done first in two-point analysis, and subsequently in a multipoint manner.
• Leppavuori et al (1999)
  • In this paper, a pseudomarker polylocus linkage analysis strategy was used in a search for genes for a form of osteoarthritis

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Chronological list of all publications

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2006

Terwilliger JD, Hiekkalinna TS (2006) An Utter Refutation of the "Fundamental Theorem of the HapMap". Eur J Hum Genet 14:426-437.

Li Z, Szaboles M, Terwilliger JD, Efstratiadis A (2006) Prostatic intraepithelial neoplasia and adenocarcinoma in mice expressing a probasin-Neu oncogenic transgene. Carcinogenesis 27:1054-1067.

Anttila V, Kalleja M, Oswell G, Kaunisto MA, Nyholt DR, Hamalainen E, Havanka H, Ilmavirta M, Terwilliger J, Sobel E, Peltonen L, Kaprio J, Farkkila M, Wessman M, Palotie A (2006) Trait components provide tools to dissect the genetic susceptibility of migraine. Am J Hum Genet 79:85-99.

Terwilliger JD, Lee JH (2006) Natural Experiments in Human Gene Mapping: The Intersection of Anthropological Genetics and Genetic Epidemiology. In Press

Hennah W, Tomppo L, Hiekkalinna T, Palo OM, Kilpinen H, Ekelund J, Tuulio-Henriksson A, Silander K, Partonen T, Paunio T, Terwilliger JD, Lonnqvist J, Peltonen L (2006) Families with the risk allele of DISC1 reveal a link between schizophrenia and another component of the same molecular pathway, NDE1. (Under review).

Paunio T, Arajarvi R, Terwilliger JD, Hiekkalinna T, Haimi P, Partonen T, Lonnqvist J, Peltonen L, Varilo T (2006) Founder effect in a complex disease: A schizophrenia study in a young founder population from Finland. (Under review)

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2005

Hiekkalinna TS, Terwilliger JD, Sammalisto S, Peltonen L, Perola M (2005) AUTOGSCAN: Powerful tools for automated genome-wide linkage and linkage disequilibrium analysis. Twin Res Hum Genet 8:16-24.

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2004

Imanishi T, Itoh T, Suzuki Y, O'Donovan C, Fukuchi S, Koyanagi KO, Barrero RA, Tamura T, Yamaguchi-Kabata Y, Tanino M, Yura K, Miyazaki S, Ikeo K, Homma K, Kasprzyk A, Nishikawa T, Hirakawa M, Thierry-Mieg J, Thierry-Mieg D, Ashurst J, Jia L, Nakao M, Thomas MA, Mulder N, Karavidopoulou Y, Jin L, Kim S, Yasuda T, Lenhard B, Eveno E, Suzuki Y, Yamasaki C, Takeda J, Gough C, Hilton P, Fujii Y, Sakai H, Tanaka S, Amid C, Bellgard M, Bonaldo Mde F, Bono H, Bromberg SK, Brookes AJ, Bruford E, Carninci P, Chelala C, Couillault C, de Souza SJ, Debily MA, Devignes MD, Dubchak I, Endo T, Estreicher A, Eyras E, Fukami-Kobayashi K, Gopinath GR, Graudens E, Hahn Y, Han M, Han ZG, Hanada K, Hanaoka H, Harada E, Hashimoto K, Hinz U, Hirai M, Hishiki T, Hopkinson I, Imbeaud S, Inoko H, Kanapin A, Kaneko Y, Kasukawa T, Kelso J, Kersey P, Kikuno R, Kimura K, Korn B, Kuryshev V, Makalowska I, Makino T, Mano S, Mariage-Samson R, Mashima J, Matsuda H, Mewes HW, Minoshima S, Nagai K, Nagasaki H, Nagata N, Nigam R, Ogasawara O, Ohara O, Ohtsubo M, Okada N, Okido T, Oota S, Ota M, Ota T, Otsuki T, Piatier-Tonneau D, Poustka A, Ren SX, Saitou N, Sakai K, Sakamoto S, Sakate R, Schupp I, Servant F, Sherry S, Shiba R, Shimizu N, Shimoyama M, Simpson AJ, Soares B, Steward C, Suwa M, Suzuki M, Takahashi A, Tamiya G, Tanaka H, Taylor T, Terwilliger JD, Unneberg P, Veeramachaneni V, Watanabe S, Wilming L, Yasuda N, Yoo HS, Stodolsky M, Makalowski W, Go M, Nakai K, Takagi T, Kanehisa M, Sakaki Y, Quackenbush J, Okazaki Y, Hayashizaki Y, Hide W, Chakraborty R, Nishikawa K, Sugawara H, Tateno Y, Chen Z, Oishi M, Tonellato P, Apweiler R, Okubo K, Wagner L, Wiemann S, Strausberg RL, Isogai T, Auffray C, Nomura N, Gojobori T, Sugano S. (2004) Integrative annotation of 21,037 human genes validated by full-length cDNA clones. PLoS Biol 2:e162.

Terwilliger JD (2004) Science and Engineering and their different roles in investigations of the genetic portion of the etiology of complex human traits. Genomics and Informatics 2:1-6.

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2003

Terwilliger JD, Weiss KM (2003). Confounding, Ascertainment Bias, and the Blind Quest for a Genetic "Fountain of Youth". Ann Med 35:532-544.

Terwilliger JD (2003). Genetic Map Ignores Evolution. Genomics and Proteomics. (Oct 2003).

Varilo T, Paunio T, Parker A, Perola M, Meyer J, Terwilliger JD, Peltonen L (2003) The interval of linkage disequilibrium (LD) detected with microsatellite and SNP markers in chromosomes of Finnish populations with different histories. Hum Molec Genet 12:51-59.

Yonan AL, Alarcon M, Cheng R, Magnusson PKE, Spence SJ, Palmer AA, Grunn A, Juo SHH, Terwilliger JD, Liu JJ, Cantor RM, Geschwind DH, Gilliam TC (2003) A genomewide screen of 245 families for autism-susceptibility loci. Am J Hum Genet 73:886-897.

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2002

Terwilliger JD, Haghighi F, Hiekkalinna TS, Göring HHH (2002) A “bias”-ed assessment of the use of SNPs in human complex traits. Curr Opin Gen Dev 12:726-734.

Terwilliger JD, Goring HHH, Magnusson PKE, Lee JH (2002) Study Design for Genetic Epidemiology and Gene Mapping: The Korean Diaspora Project. Shengming kexue yanjiu (Life Science Research) 6:95-115

Enattah NS, Sahi T, Savilahti E, Terwilliger JD, Peltonen L, Järvelä I (2002) Identification of a variant associated with adult type hypolactasia. Nat Genet 30:233-237.

Liu JJ, Juo SH, Holopainen P, Terwilliger JD, Tong X, Grunn A, Brito M, Green P, Mustalahti K, Mäki M, Gilliam TC, Partanen J (2002) Genome wide linkage analysis of celiac disease in Finnish families. Am J Hum Genet 70:51-59.

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2001

Terwilliger JD (2001) On the resolution and feasibility of genome scanning approaches. Adv Genet 42:351-391.

Almasy L, Terwilliger JD, Nielsen D, Dyer TD, Zaykin D, Blangero J (2001) GAW12: Simulated genome scan, sequence, and family data for a common disease. Genetic Epidemiol 21:S332-S338.

Göring HHH, Terwilliger JD, Blangero J (2001) Large Upward Bias in Estimation of Locus-Specific Effects from Genomewide Scans. Am J Hum Genet 69:1357-1369.

Liu JJ, Juo SH, Terwilliger JD, Grunn A, Tong XM, Brito M, Loth JE, Kanyas K, Lerer B, Endicott J, Penchaszadeh G, Gilliam TC, Baron M (2001) A follow-up linkage study supports evidence for a bipolar affective disorder locus on chromosome 21q22. Am J Med Genet 105:189-194.

Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Developmental Biology 229:141-162.

Paavola P, Heliö T, Kiuru M, Halme L, Turunen U, Terwilliger J, Karvonen A-L, Julkunen R, Niemelä S, Nurmi H, Färkkilä M, Kontula K (2001) Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21. Eur J Hum Genet 9:328-334

Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen J, Rinard K, Foti A, Terwilliger JD, Juvonen H, Suvisaari J, Arajärvi R, Suokas J, Partonen T, Lönnqvist J, Meyer J, Peltonen L (2001) Genome-wide scan in a nation-wide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosome 2q and 5q. Hum Molec Genet 10:3037-3048.

Sokolová J, Janošíkova B, Terwilliger JD, Freiberger T, Kraus JP, Kožich V (2001) Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles. Human Mutation 18:548-549.

Thomas DC, Borecki IB, Thomson G, Weiss K, Almasy L, Blangero J, Nielsen D, Terwilliger J, Zaykin D, MacCluer J (2001) Evolution of the simulated data problem. Genetic Epidemiol 21:S325-S331.

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2000

Terwilliger JD (2000) A likelihood-based extended admixture model of oligogenic inheritance in “model-based” or “model-free” analysis. Eur J Hum Genet 8:399-406.

Terwilliger JD (2000) Inflated false-positive rates in Hardy-Weinberg and linkage-equilibrium tests due to sampling on the basis of rare familial phenotypes in finite populations. Am J Hum Genet 67:258-259

Terwilliger JD (2000) Reply to Deng and Chen. Am J Hum Genet 67:261-262

Terwilliger JD, Göring HHH (2000) Gene mapping in the 20th and 21st centuries: Statistical methods, data analysis, and experimental design. Hum Biol 72:63-132.

Terwilliger JD, Rzhetsky A, Lee JH (2000) Gene-environment interaction in complex traits: A study of the Korean diaspora. Am J Hum Genet 67:1241.

Göring HHH, Terwilliger JD (2000) Linkage analysis in the presence of errors I: Complex-valued recombination fractions and complex phenotypes. Am J Hum Genet 66:1095-1106 ( Erratum)

Göring HHH, Terwilliger JD (2000) Linkage analysis in the presence of errors II: Marker-locus genotyping errors modeled with hypercomplex recombination fractions. Am J Hum Genet 66:1107-1118 (Erratum)

Göring HHH, Terwilliger JD (2000) Linkage analysis in the presence of errors III: Marker loci and their map as nuisance parameters. Am J Hum Genet 66:1298-1309

Göring HHH, Terwilliger JD (2000) Linkage analysis in the presence of errors IV: Joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am J Hum Genet 66:1310-1327

Weiss KM, Terwilliger JD (2000) How many diseases do you have to study to map one gene with SNPs? Nat Genet 26:151-158.

Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD, Juvonen H, Varilo T, Arajärvi R, Kokko-Sahin M-L, Lönnqvist J, Peltonen L. (2000) Genome-wide scan for schizophrenia in the Finnish population: Evidence for a locus on chromosome 7q22. Hum Molec Genet 9:1049-1057.

Lindqvist AKB, Steinsson K, Johanneson B, Kristjánsdóttir H, Àrnasson A, Gröndal G, Jonasson I, Magnusson V, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Terwilliger JD, Gyllensten UB, Alarcón-Riquelme ME (2000) A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J Autoimm 14:169-178.

Magnusson V, Lindqvist AK, Castillejo-Lopez C, Kristjansdottir H, Steinsson K, Grondal G, Sturfelt G, Truedsson L, Svenungsson E, Lundberg I, Gunnarsson I, Bolstad AI, Haga HJ, Jonsson R, Klareskog L, Alcocer-Varela J, Alarcon-Segovia D, Terwilliger JD, Gyllensten UB, Alarcon-Riquelme ME (2000) Fine Mapping of the SLEB2 Locus Involved in Susceptibility to Systemic Lupus Erythematosus. Genomics 70:307-314

Moses EK, Lade JA, Guo G, Wilton AN, Grehan M, Freed K, Borg A, Terwilliger JD, North R, Cooper DW, Brennecke SP (2000) A Genome Scan in Families from Australia and New Zealand Confirms the Presence of a Maternal Susceptibility Locus for Pre-Eclampsia, on Chromosome 2. Am J Hum Genet 67 1581-1585.

Pajukanta P, Cargill M, Viitanan L, Nuotio I, Kareinen A, Perola M, Terwilliger JD, Kempas E, Daly M, Lilja M, Rioux J, Brettin T, Viikari JSA, Rönnenmaa T, Laakso M, Lander ES, Peltonen L (2000) Two loci on chromosomes 2 and X for premature coronary heart disease identified in early and late settlement populations of Finland. Am J Hum Genet 67:1481-1493

Perola M, Kainulainen K, Pajukanta P, Terwilliger JD, Hiekkalinna T, Ellonen P, Kaprio J, Koskenvuo M, Kontula K, Peltonen L (2000) Genome-wide scan of predisposing loci for increased diastolic blood pressure in Finnish siblings. J Hypertension 18:1579-1585

Varilo T, Laan M, Hovatta IM, Wiebe V, Terwilliger JD, Peltonen L (2000) Linkage disequilibrium in isolated populations: Finland and a young subpopulation of Kuusamo. Eur J Hum Genet 8:604-612

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1999

Aita VM, Liu JJ, Knowles JA, Terwilliger JD, Baltazar R, Grunn A, Loth JE, Kanyas K, Lerer B, Endicott J, Wang ZY, Penchaszadeh G, Gilliam TC, Baron M (1999) A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet 64:210-217.

Hovatta IM, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R, Juovinen H, Kokko Sahin ML, Vaisanen L, Mannila H, Lonnqvist J, Peltonen L (1999) A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation suggesting multiple susceptibility loci. Am J Hum Genet 65:1114-1124.

Kainulainen K, Perola M, Terwilliger JD, Kaprio J, Koskenvuo M, Syvanen AC, Vartiainen E, Peltonen L, Kontula K (1999) Evidence for involvement of the Type-I angiotensin II receptor locus in Essential Hypertension. Hypertension 33:844-849.

Leppavuori J, Kujala U, Kinnunen J, Kaprio J, Nissila M, Heliovaara M, Klinger N, Partanen J, Terwilliger JD, Peltonen L (1999) Genome scan for predisposing loci for distal interphalangeal joint osteoarthritis: Evidence for a locus on 2q. Am J Hum Genet 65:1060-1067.

Nakagawa M. Takashima H, Suehara M, Saito M, Saito A, Kanzato N, Matsuzaki T, Hirata K, Izumo S, Terwilliger JD, Osame M. (1999) Hereditary motor and sensory neuropathy with proximal dominant involvement: Clinical, pathological, and genetic features. Ann NY Acad Sci 883:449-452.

Pajukanta P, Terwilliger JD, Perola M, Hiekkalinna T, Nuotio I, Ellonen P, Parkkonen M, Hartiala J, Porkka K, Laakso M, Viikari J, Ehnholm C, Taskinen MR, Peltonen L (1999) Genome-wide scan for familial combined hyperlipidemia genes in Finnish families suggesting multiple susceptibility loci influencing triglycerides, cholesterol, and apolipoprotein B levels. Am J Hum Genet 64:1453-1463.

Takashima H, Nakagawa M, Suehara M, Saito M, Saito A, Kansato N, Matsuzaki T, Hirata K, Terwilliger JD, Osame M (1999) Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1. Neuromuscular Disord 9:368-371.

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1998

Terwilliger JD, Weiss KM (1998) Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr Opin Biotechnol 9: 578-594.

Terwilliger JD (1998) Linkage analysis - Model Based. In: Encyclopedia of Biostatistics. New York, NY: Wiley.

Terwilliger JD, Zöllner S, Laan M, Pääbo S (1998) Mapping genes through the use of linkage disequilibrium generated by genetic drift: ‘Drift mapping’ in small populations with no demographic expansion. Hum Hered 48:138-154.

Hovatta IM, Lichtermann D, Juvonen H, Suvisaari J, Terwilliger JD, Arajarvi R, Kokko-Sahin ML, Ekelund J, Lonnqvist J, Peltonen L (1998) Linkage analysis of putative schizophrenia candidate regions on chromosomes 3p, 5q, 6p, 8p, 20p, and 22q in a population-based sampled Finnish family set. Mol Psychiatry 3:452-457.

Lichtermann D, Hovatta IM, Terwilliger JD, Peltonen L, Lonnqvist J (1998) Concordance for sex and the pseudoautosomal gene hypothesis revisited: No evidence of increased sex concordance in a nationwide Finnish sample of siblings with paternally derived schizophrenia. Am J Psychiatry 155:1365-1375.

Pajukanta P, Nuotio I, Terwilliger JD, Porkka KVK, Ylitalo K, Pihjalamaki J, Suomalainen AJ, Syvanen AC, Lehtimaki T, Viikari JSA, Laakso M, Taskinen MR, Ehnholm C, Peltonen L (1998) Linkage of familial combined hyperlipidemia to chromosome 1q21-q23. Nat Genet 18:369-373.

Pastinen T, Perola M, Nuni P, Terwilliger JD, Salomaa V, Vartiainen E, Peltonen L, Syvanen AC (1998) Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. Hum Molec Genet 7:1453-1462.

Pekkarinen P, Kestila M, Paloneva J, Terwilliger JD, Varilo T, Jarvi O, Hakola P, Peltonen L (1998) Fine-scale mapping of a novel dementia gene, PLO-SL, by linkage disequilibrium. Genomics 54:307-315.

Pekkarinen P, Hovatta IM, Hakola P, Järvi O, Kestilä M, Lenkkeri U, Adolfsson R, Holmgren G, Nylander PO, Tranebjærg L, Terwilliger JD, Lönnqvist J, Peltonen L (1998) Assignment of the locus for PLO-SL, a frontal-lobe dementia with bone cysts, to 19q13. Am J Hum Genet 62:362-372.

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1997

Terwilliger JD (1997) Review of: Genetic Variation and Human Disease: Principles and evolutionary approaches by KM Weiss. Am J Hum Genet 60:1565-1566.

Terwilliger JD (1997) Mapping genes predisposing to complex traits in extreme population isolates. CSC News June 1997: 23-26.

Terwilliger JD, Shannon WD, Lathrop GM, Nolan JP, Goldin LR, Chase GA, Weeks DE (1997) True and false positive peaks in genomewide scans: Applications of length-biased sampling to linkage mapping. Am J Hum Genet 61:430-438.

Hovatta IM, Terwilliger JD, Lichtermann D, Makikyro T, Suvisaari J, Peltonen L, Lonnqvist J (1997) Schizophrenia in the genetic isolate of Finland. Am J Med Genet 74:353-360.

Julier C, Delepine M, Keavney B, Terwilliger JD, Davis S, Weeks DE, Bui T, Jeunemaitre X, Velho G, Froguel P, Ratcliffe P, Corvol P, Soubrier F, Lathrop GM (1997) Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10. Hum Molec Genet 6:2077-2086.

Kuokkanen S, Gschwend M, Rioux JD, Daly MJ, Terwilliger JD, Tienari PJ, Wikström J, Palo J, Stein LD, Hudson TJ, Lander ES, Peltonen L (1997) Genomewide scan of multiple sclerosis in Finnish multiplex families. Am J Hum Genet 61:1379-1387.

Trembath RC, Clough RL, Rosbotham JL, Jones AB, Camp RDR, Frodsham A, Browne J, Barber R, Terwilliger JD, Lathrop GM, Barker JNWN (1997) Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two-stage genome-wide search in psoriasis. Hum Molec Genet 6:813-820.

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1996

Lathrop GM, Terwilliger JD, Weeks DE (1996) Multifactorial inheritance and genetic analysis of multifactorial disease. In: Rimoin DL, Connor JM, Pyeritz RE (Eds) Emery and Rimoin’s Principles and Practice of Medical Genetics. New York: Churchill-Livingstone. pp. 333-346.

Terwilliger JD (1996) Likelihood ratio tests for linkage and linkage disequilibrium: Asymptotic distribution and power - Reply. Am J Hum Genet 58:1095-1096.

Kuokkanen S, Sundvall M, Terwilliger JD, Tienari PJ, Wikstrom J, Holmdahl R, Petterson U, Peltonen L (1996) A putative vulnerability locus to multiple sclerosis maps to 5p14-p12 in a region syntenic to the murine locus Eae2. Nat Genet 13:477-480.

Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP (1996) Two-stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7, and 12. Nat Genet 14:199-202.

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1995

Terwilliger JD (1995) A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet 56:777-787. ( Erratum)

Haberhausen G, Schmitt I, Kohler A, Peters U, Rider S, Chelly J, Terwilliger JD, Monaco AP, Muller U (1995) Assignment of the dystonia-parkinsonism syndrom locus DYT3, to a small region within a 1.8-Mb contig of Xq13.1. Am J Hum Genet 57:644-650.

Hovnanian A, Hilal L, Blanchet-Bardon C, Bodemer C, deProst Y, Stark CA, Christiano AM, Dommergues M, Terwilliger JD, Izquierdo L, Conteville P, Dumez Y, Uitto J, Goossens M (1995) DNA-based prenatal diagnosis of generalized recessive dystrophic epidermolysis bullosa in six pregnancies at risk for recurrence. J Invest Dermatol 104: 456-461.

Nikali K, Suomalainen A, Terwilliger JD, Koskinen T, Weissenbach J, Peltonen L (1995) Random search for shared chromosomal segments in four affected individuals: The assignment of a new hereditary ataxia locus. Am J Hum Genet 56:1088-1095.

Pekkarinen P, Terwilliger JD, Bredbacka PE, Lonnqvist J, Peltonen L (1995) Evidence of a predisposing locus to bipolar disorder on Xq24-q27.1 in an extended Finnish pedigree. Gen Res 5:105-115.

Raha-Choudhury R, Bowen DJ, Stone C, Pointon JJ, Terwilliger JD, Shearman JD, Robson KJH, Bonford A, Worwood M (1995) New polymorphic microsatellite markers place the haemochromatosis gene telomeric to D6S105. Hum Molec Genet 4:1869-1874.

Speer MC, Terwilliger JD, Ott J (1995) Data simulation for GAW9 problems 1 and 2. Genet Epidemiol 12:561-564.

Vaxillaire M, Boccio V, Philippi A, Vigoroux C, Terwilliger JD, Passa P, Beckmann JS, Velho G, Lathrop GM, Froguel P (1995) A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet 9:418-423.

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1994

Terwilliger JD, Ott J (1994) Handbook of Human Genetic Linkage. Baltimore, MD: Johns Hopkins University Press.

Schork NJ, Boehnke M, Terwilliger JD, Ott J (1994) 2-Locus versus one-locus lods for complex traits – reply. Am J Hum Genet 55: 856-858.

James MR, Richard CW, Schott JJ, Yousry C, Clark K, Bell J, Terwilliger JD, Hazan J, Dubay C, Vignal A, Agrapart M, Imai T, Nakamura Y, Polymeropoulos M, Weissenbach J, Cox DR, Lathrop GM (1994) A radiation hybrid map of 506 STS markers spanning human chromosome 11. Nat Genet 8:70-76.

Tienari PJ, Terwilliger JD, Ott J, Palo J, Peltonen L (1994) Two-locus linkage analysis in multiple sclerosis. Genomics 19:320-325.

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1993

Terwilliger JD, Ott J (1993) A novel polylocus method for linkage analysis using the lod score or affected sib pair method. Genet Epidemiol 10:477-482.

Terwilliger JD, Speer MC, Ott J (1993) Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 10:217-224.

Bunge S, Wedermann H, David D, Terwilliger JD, van den Born LI, Aulehla-Scholz C, Samanns C, Horn M, Ott J, Schwinger E, Schinzel A, Denton MJ, Gal A (1993) Molecular analysis and genetic mapping of the rhodopsin gene in families with autosomal dominant retinitis pigmentosa. Genomics 17:230-233.

Schork NJ, Boehnke M, Terwilliger JD, Ott J (1993) Two-trait-locus linkage analysis: A powerful strategy for mapping complex genetic traits. Am J Hum Genet 53:1127-1136.

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1992

Ott J, Terwilliger JD (1992)Assessing the evidence for linkage in psychiatric genetics. In: Mendlewicz J, Hippius H (Eds) Genetic Research in Psychiatry. Springer-Verlag: Berlin, pp.245-249.

Terwilliger JD, Ding Y, Ott J (1992) On the relative importance of marker heterozygosity and intermarker distance in gene mapping. Genomics 13:951-956.

Terwilliger JD, Ott J (1992) A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations. Hum Hered 42:337-346.

Terwilliger JD, Ott J (1992) A multisample bootstrap approach to the estimation of maximized-over-models lod score distributions. Cytogenet Cell Genet 59:142-144.

Ellison KA, Fill CP, Terwilliger JD, DeGennaro LJ, Martin-Gallardo A, Anvret M, Percy AK, Ott J, Zoghbi H (1992) Examination of X chromosome markers in Rett syndrome: Exclusion mapping with a novel variation on multilocus linkage analysis. Am J Hum Genet 50:278-287.

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1991

Delisi LE, Crow TJ, Davies KE, Terwilliger JD, Ott J, Ram R, Flint T, Boccio A (1991) No genetic linkage detected for schizophrenia to Xq27-q28. Brit J Psych 158:630-634.

Passos-Bueno MR, Byth B, Love D, Terwilliger JD, Ott J, Rapaport D, Vainzof M, Zatz M, Davies KE (1991) Exclusion of the gene responsible for facioscapulohumeral muscular dystrophy (FSH) at 6q23-q27. J Neurol Sci 102:206-208.

Passos-Bueno MR, Terwilliger JD, Ott J, Vainzof M, Love DR, Davies KE, Zatz M (1991) Linkage analysis in families with autosomal recessive limb-girdle muscular dystrophy (LGMD) and 6q probes flanking the dystrophin-related sequence. Am J Med Genet 38:140-146.

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1990

Kwan SP, Terwilliger JD, Parmley R, Raghu G, Sandkuyl LA, Ott J, Ochs H, Wedgwood R, Rosen F (1990) Identification of a closely linked DNA marker, DXS178, to further refine the x-linked agammaglobulinemia locus. Genomics 6:238-242.

Ott J, Bhattacharya S, Chen JD, Denton MJ, Donald J, Dubay C, Farrar GJ, Fishman GA, Frey D, Gal A, Humphries P, Jay B, Jay M, Litt M, Mächler M, Musarella M, Neugebauer M, Nussbaum RL, Terwilliger JD, Weleber RG, Wirth B, Wong F, Worton RG, Wright AF. (1990) Localizing multiple X chromosome-linked retinitis pigmentosa loci using multilocus homogeneity tests. Proc Natl Acad Sci USA 87:701-704.

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1989

Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, Westaway D, Ott J, Prusiner SB (1989) Linkage of a prion protein missense variant to Gerstmann-Straüssler syndrome. Nature 338:342-345.

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