Linkage analysis of adult height in a large pedigree from a Dutch genetically isolated population

Despite extensive research of genetic determinants of human adult height, the genes identified up until now allow to predict only a small proportion of the trait’s variance. To identify new genes we analyzed 2,486 genotyped and phenotyped individuals in a large pedigree including 23,612 members in 18 generations. The pedigree was derived from a young genetically isolated Dutch population, where genetic heterogeneity is expected to be low and linkage disequilibrium has been shown to be increased. Complex segregation analysis confirmed high heritability of adult height, and suggested mixed model of height inheritance in this population. The estimates of the model parameters obtained from complex segregation analysis were used in parametric linkage analysis, which highlighted three genome-wide significant and additionally at least four suggestive loci involved in height. Significant peaks were located at the chromosomal regions 1p32 (LOD score = 3.35), 2p16 (LOD score = 3.29) and 16q24 (LOD score = 3.94). For the latter region, a strong association signal (FDR q < 0.05) was obtained for 19 SNPs, 17 of them were located in the CDH13 (cadherin 13) gene of which one (rs1035569) explained 1.5% of the total height variance.

[1]  Cornelia M van Duijn,et al.  The effect of genetic drift in a young genetically isolated population. , 2005, Annals of human genetics.

[2]  E. Kobyliansky,et al.  Major gene control of human body height, weight and BMI in five ethnically different populations , 1998, Annals of human genetics.

[3]  L. Penrose,et al.  THE CORRELATION BETWEEN RELATIVES ON THE SUPPOSITION OF MENDELIAN INHERITANCE , 2022 .

[4]  Yurii S. Aulchenko,et al.  Solution for underflow problem in linkage and segregation analysis , 2006, Comput. Biol. Chem..

[5]  Jonathan C. Cohen,et al.  Genome‐wide Linkage and Association Analyses to Identify Genes Influencing Adiponectin Levels: The GEMS Stud , 2009, Obesity.

[6]  C. V. van Duijn,et al.  Ignoring Distant Genealogic Loops Leads to False‐positives in Homozygosity Mapping , 2006, Annals of human genetics.

[7]  M. King,et al.  Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.

[9]  R. Olshen,et al.  Combined analysis of genomewide scans for adult height: results from the NHLBI Family Blood Pressure Program , 2003, European Journal of Human Genetics.

[10]  S. Heath,et al.  Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J R O'Connell,et al.  PedCheck: a program for identification of genotype incompatibilities in linkage analysis. , 1998, American journal of human genetics.

[12]  Kenneth Lange,et al.  Use of population isolates for mapping complex traits , 2000, Nature Reviews Genetics.

[13]  S. Seal,et al.  Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. , 1994, Science.

[14]  D. Hunter,et al.  The genetics of intervertebral disc degeneration. Associated genes. , 2008, Joint, bone, spine : revue du rhumatisme.

[15]  S. Goodman,et al.  Toward Evidence-Based Medical Statistics. 2: The Bayes Factor , 1999, Annals of Internal Medicine.

[17]  Jennifer R. Harris,et al.  Heritability of Adult Body Height: A Comparative Study of Twin Cohorts in Eight Countries , 2003, Twin Research.

[18]  P. Sham.  Statistics in human genetics , 1997 .

[19]  Hui Shen,et al.  Genetic Dissection of Human Stature in a Large Sample of Multiplex Pedigrees , 2004, Annals of human genetics.

[20]  K. Pearson,et al.  ON THE LAWS OF INHERITANCE IN MAN I. INHERITANCE OF PHYSICAL CHARACTERS , 1903 .

[21]  Chiara Sabatti,et al.  Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association studies , 2006, Nature Genetics.

[22]  W. G. Hill,et al.  Genome partitioning of genetic variation for height from 11,214 sibling pairs. , 2007, American journal of human genetics.

[23]  J. Kaprio,et al.  Relative effect of genetic and environmental factors on body height: differences across birth cohorts among Finnish men and women. , 2000, American journal of public health.

[24]  Christian B. Woods,et al.  Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors , 2006, Oncogene.

[25]  F. Galton.  Regression Towards Mediocrity in Hereditary Stature. , 1886 .

[26]  N E Morton,et al.  Analysis of family resemblance. 3. Complex segregation of quantitative traits. , 1974, American journal of human genetics.

[27]  D. Beier,et al.  The genes encoding alpha 2(IX) collagen (COL9A2) map to human chromosome 1p32.3-p33 and mouse chromosome 4. , 1994, Genomics.

[28]  M. McGue,et al.  A cross-sectional examination of height, weight, and body mass index in adult twins. , 1995, The journals of gerontology. Series A, Biological sciences and medical sciences.

[29]  Aribert Rothenberger,et al.  Genome‐wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[30]  M. Kendall,et al.  The advanced theory of statistics , 1945 .

[31]  L. Cardon,et al.  Linkage disequilibrium in young genetically isolated Dutch population , 2004, European Journal of Human Genetics.

[32]  A. de la Chapelle,et al.  Clinical features of primary ovarian failure caused by a point mutation in the follicle-stimulating hormone receptor gene. , 1996, The Journal of clinical endocrinology and metabolism.

[33]  P. Visscher,et al.  Within-family outliers: segregating alleles or environmental effects? A linkage analysis of height from 5815 sibling pairs , 2008, European Journal of Human Genetics.

[34]  R. Elston,et al.  A general model for the genetic analysis of pedigree data. , 1971, Human heredity.

[35]  Manuel A. R. Ferreira,et al.  Meta-analysis of genome-wide linkage studies of asthma and related traits , 2008, Respiratory research.

[36]  Leonid Kalichman.  The Genetics of Intervertebral Disc Degeneration , 2009 .

[37]  F. Lecanda,et al.  Relative abundance of different cadherins defines differentiation of mesenchymal precursors into osteogenic, myogenic, or adipogenic pathways , 2000, Journal of cellular biochemistry.

[38]  T. Nakajima,et al.  Large‐Scale Screening for Candidate Genes of Ossification of the Posterior Longitudinal Ligament of the Spine , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[39]  J. Minna,et al.  Loss of expression and aberrant methylation of the CDH13 (H-cadherin) gene in breast and lung carcinomas. , 2001, Cancer research.

[40]  Yurii S. Aulchenko,et al.  A Genomic Background Based Method for Association Analysis in Related Individuals , 2007, PloS one.

[41]  B. Franke,et al.  Meta‐analysis of genome‐wide linkage scans of attention deficit hyperactivity disorder , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[42]  R. Fisher.  XV.—The Correlation between Relatives on the Supposition of Mendelian Inheritance. , 1919, Transactions of the Royal Society of Edinburgh.

[43]  D. Weeks,et al.  Linkage analysis of adult height with parent-of-origin effects in the Framingham Heart Study , 2003, BMC Genetics.

[44]  Cornelia M. van Duijn,et al.  A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis , 2001, Nature Genetics.

[45]  E A Thompson,et al.  Monte Carlo estimation of mixed models for large complex pedigrees. , 1994, Biometrics.

[46]  R. Elston,et al.  Linkage analysis with an alternative formulation for the mixed model of inheritance: the finite polygenic mixed model. , 1995, Genetics.

[47]  G. Abecasis,et al.  Merlin—rapid analysis of dense genetic maps using sparse gene flow trees , 2002, Nature Genetics.

[48]  R. Recker,et al.  IBD5 risk haplotype and CARD15 variants add up to a bigger chance of Crohn’s disease , 2003, Journal of medical genetics.

[49]  C. Lannér,et al.  Genetic validity of RAPD markers at the intra- and inter-specific level in wild Brassica species with n=9 , 1996, Theoretical and Applied Genetics.

[50]  D. Rao,et al.  A variance components/major locus likelihood approximation on quantitative data , 1991, Genetic epidemiology.

[51]  Fan Liu,et al.  Breaking Loops in Large Complex Pedigrees , 2007, Human Heredity.

[52]  J. Houwing-Duistermaat,et al.  Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. , 2001, American journal of human genetics.

[53]  R. Elston,et al.  The finite polygenic mixed model: An alternative formulation for the mixed model of inheritance , 1994, Theoretical and Applied Genetics.

[54]  C. Gieger,et al.  Identification of ten loci associated with height highlights new biological pathways in human growth , 2008, Nature Genetics.

[55]  David M. Evans,et al.  Genome-wide association analysis identifies 20 loci that influence adult height , 2008, Nature Genetics.

[56]  G. Byrnes,et al.  Comprehensive multi-stage linkage analyses identify a locus for adult height on chromosome 3p in a healthy Caucasian population , 2007, Human Genetics.

[57]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[58]  G. Willemsen,et al.  QTLs for height: results of a full genome scan in Dutch sibling pairs , 2004, European Journal of Human Genetics.

[59]  K. Roeder,et al.  Genomic Control for Association Studies , 1999, Biometrics.

[60]  B. Oostra,et al.  DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism , 2003, Neurological Sciences.

[61]  M. Philippova,et al.  Structure and Functions of Classical Cadherins , 2001, Biochemistry (Moscow).

[62]  Yao-Zhong Liu,et al.  A major gene model of adult height is suggested in Chinese , 2004, Journal of Human Genetics.

[63]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[64]  J. Hebebrand,et al.  Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies. , 2006, Human molecular genetics.

[65]  R. C. Elston,et al.  An algorithm to approximate the likelihood for pedigree data with loops by cutting , 2004, Theoretical and Applied Genetics.

[66]  J. P. Lomenick,et al.  Transcription factor FOXF1 regulates growth hormone variant gene expression. , 2006, American journal of physiology. Endocrinology and metabolism.

[67]  C. Cannings,et al.  Probability functions on complex pedigrees , 1978, Advances in Applied Probability.

[68]  P. Jatlow,et al.  A Placebo-Controlled Trial of Bupropion Combined with Nicotine Patch for Smoking Cessation in Schizophrenia , 2008, Biological Psychiatry.

[69]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[70]  M. McCarthy,et al.  Evidence for linkage of stature to chromosome 3p26 in a large U.K. Family data set ascertained for type 2 diabetes. , 2002, American journal of human genetics.

[71]  K. Phillips,et al.  Quantitative genetic analysis of longitudinal trends in height: preliminary results from the Louisville Twin Study. , 1990, Acta geneticae medicae et gemellologiae.

[72]  D. Rao,et al.  Genetic epidemiology of breast cancer: Segregation analysis of 200 Danish pedigrees , 1984, Genetic epidemiology.

[73]  Y. Ohtsuki,et al.  Expression of T‐Cadherin (CDH13, H‐Cadherin) in Human Brain and Its Characteristics as a Negative Growth Regulator of Epidermal Growth Factor in Neuroblastoma Cells , 2000, Journal of neurochemistry.

[74]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[75]  Nadezhda M. Belonogova,et al.  Optimal peeling order for pedigrees with incomplete genotypic information , 2007, Comput. Biol. Chem..

[76]  P. Rudan,et al.  Complex segregation analysis of body height, weight and BMI in pedigree data from Middle Dalmatia, Croatia. , 2003, Collegium antropologicum.

[77]  L. Peltonen,et al.  A male-specific quantitative trait locus on 1p21 controlling human stature , 2005, Journal of Medical Genetics.

[78]  A. Hofman,et al.  Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. , 2009, Human molecular genetics.

[79]  Hui Shen,et al.  A whole-genome linkage scan suggests several genomic regions potentially containing QTLs underlying the variation of stature. , 2002, American journal of medical genetics.

[80]  S J Hasstedt,et al.  A mixed-model likelihood approximation on large pedigrees. , 1982, Computers and biomedical research, an international journal.

[81]  Maurice G. Kendall,et al.  The advanced theory of statistics , 1945 .

[82]  Yurii S. Aulchenko,et al.  BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm108 Genetics and population analysis GenABEL: an R library for genome-wide association analysis , 2022 .

[83]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[84]  Hui Shen,et al.  Genetic linkage of human height is confirmed to 9q22 and Xq24 , 2006, Human Genetics.

[85]  S. Tomatsu,et al.  Growth charts for patients affected with Morquio A disease , 2008, American journal of medical genetics. Part A.

[86]  C. V. van Duijn,et al.  The Effect of Genetic Drift in a Young Genetically Isolated Population , 2005 .

[87]  S. Leal.  Genetics and Analysis of Quantitative Traits , 2001 .

[88]  Hideo Fujita,et al.  Foxc2 Is a Common Mediator of Insulin and Transforming Growth Factor &bgr; Signaling to Regulate Plasminogen Activator Inhibitor Type I Gene Expression , 2006, Circulation research.

[89]  Caryn Lerman,et al.  Molecular genetics of successful smoking cessation: convergent genome-wide association study results. , 2008, Archives of general psychiatry.

[90]  P. Sham,et al.  Model-free linkage analysis using likelihoods. , 1995, American journal of human genetics.

[91]  Sanjay Shete,et al.  Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. , 2004, American journal of human genetics.

[92]  L. Peltonen,et al.  Quantitative-trait-locus analysis of body-mass index and of stature, by combined analysis of genome scans of five Finnish study groups. , 2001, American journal of human genetics.

[93]  R. C. Elston,et al.  An approximation to the likelihood for a pedigree with loops , 1996, Theoretical and Applied Genetics.

[94]  D. Postma,et al.  Major recessive gene(s) with considerable residual polygenic effect regulating adult height: confirmation of genomewide scan results for chromosomes 6, 9, and 12. , 2002, American journal of human genetics.

[95]  E. Lander,et al.  Genomewide linkage analysis of stature in multiple populations reveals several regions with evidence of linkage to adult height. , 2001, American journal of human genetics.

[96]  J M Lalouel,et al.  Robustness and power of the unified model in the analysis of quantitative measurements. , 1986, American journal of human genetics.

[97]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.