Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts,

Slides:

Advertisements

Similar presentations

Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts, Kristel.

Advertisements

Refinement of the Chromosome 5p Locus for Familial Calcium Pyrophosphate Dihydrate Deposition Disease L.J. Andrew, V. Brancolini, L. Serrano de la Pena,

Copyright © 2001 American Medical Association. All rights reserved.

The Gene for Glycogen-Storage Disease Type 1b Maps to Chromosome 11q23

Identification of a Major Susceptibility Locus for Restless Legs Syndrome on Chromosome 12q Alex Desautels, Gustavo Turecki, Jacques Montplaisir, Adolfo.

A Novel Locus for Familial Amyotrophic Lateral Sclerosis, on Chromosome 18q Collette K. Hand, Jawad Khoris, François Salachas, François Gros-Louis, Ana.

Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity Kathrin Saar, Lihadh.

Genetic Linkage of Paget Disease of the Bone to Chromosome 18q

Use of Homozygosity Mapping to Identify a Region on Chromosome 1 Bearing a Defective Gene That Causes Autosomal Recessive Homozygous Hypercholesterolemia.

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

Localization of the Gene for Sclerosteosis to the van Buchem Disease–Gene Region on Chromosome 17q12–q21 Wendy Balemans, Jenneke Van Den Ende, Auristela.

Soraya Beiraghi, Swapan K. Nath, Matthew Gaines, Desh D

Frances Busfield, David L. Duffy, Janine B. Kesting, Shelley M

Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p Shenghan Chen, William G. Ondo, Shaoqi Rao,

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

C. M. van Duijn, M. C. J. Dekker, V. Bonifati, R. J. Galjaard, J. J

A Novel Alu-Like Element Rearranged in the Dystrophin Gene Causes a Splicing Mutation in a Family with X-Linked Dilated Cardiomyopathy Alessandra Ferlini,

I. Silveira, I. Alonso, L. Guimarães, P. Mendonça, C. Santos, P

The Gene for Glycogen-Storage Disease Type 1b Maps to Chromosome 11q23

Mapping of Primary Congenital Lymphedema to the 5q35.3 Region

The Gene for Severe Combined Immunodeficiency Disease in Athabascan-Speaking Native Americans Is Located on Chromosome 10p Lanying Li, Dennis Drayna,

Shirley Rainier, Jing-Hua Chai, Debra Tokarz, Robert D

Complement Factor H Gene Mutation Associated with Autosomal Recessive Atypical Hemolytic Uremic Syndrome Lihua Ying, Yitzhak Katz, Menachem Schlesinger,

A Gene Mutated in Nephronophthisis and Retinitis Pigmentosa Encodes a Novel Protein, Nephroretinin, Conserved in Evolution Edgar Otto, Julia Hoefele,

Attention-Deficit/Hyperactivity Disorder in a Population Isolate: Linkage to Loci at 4q13.2, 5q33.3, 11q22, and 17p11 Mauricio Arcos-Burgos, F. Xavier.

Evidence for a Nonallelic Heterogeneity of Epidermodysplasia Verruciformis with Two Susceptibility Loci Mapped to Chromosome Regions 2p21–p24 and 17q25

Structure of the GM2A Gene: Identification of an Exon 2 Nonsense Mutation and a Naturally Occurring Transcript with an In-Frame Deletion of Exon 2 Biao.

A Mutation in the Fibroblast Growth Factor 14 Gene Is Associated with Autosomal Dominant Cerebral Ataxia John C. van Swieten, Esther Brusse, Bianca M.

Howard B. Yeon, Noralane M. Lindor, J.G. Seidman, Christine E. Seidman

Pseudoexon Activation as a Novel Mechanism for Disease Resulting in Atypical Growth- Hormone Insensitivity Louise A. Metherell, Scott A. Akker, Patricia.

John D. Rioux, Valerie A. Stone, Mark J

Familial Juvenile Hyperuricemic Nephropathy: Localization of the Gene on Chromosome 16p11.2—and Evidence for Genetic Heterogeneity Blanka Stibůrková,

A Gene for Familial Juvenile Polyposis Maps to Chromosome 18q21.1

A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

The Gene for Human Fibronectin Glomerulopathy Maps to 1q32, in the Region of the Regulation of Complement Activation Gene Cluster Martin Vollmer, Martin.

Two Families with Familial Amyotrophic Lateral Sclerosis Are Linked to a Novel Locus on Chromosome 16q Deborah M. Ruddy, Matthew J. Parton, Ammar Al-Chalabi,

Assessment of the Effect of Age at Onset on Linkage to Bipolar Disorder: Evidence on Chromosomes 18p and 21q Ping-I Lin, Melvin G. McInnis, James B.

Airong Li, Sonia Davila, Laszlo Furu, Qi Qian, Xin Tian, Patrick S

Familial Syndromic Esophageal Atresia Maps to 2p23-p24

Mutation of Solute Carrier SLC16A12 Associates with a Syndrome Combining Juvenile Cataract with Microcornea and Renal Glucosuria Barbara Kloeckener-Gruissem,

A Locus for Hereditary Sensory Neuropathy with Cough and Gastroesophageal Reflux on Chromosome 3p22-p24 C. Kok, M.L. Kennerson, P.J. Spring, A.J. Ing,

A Novel Locus for Familial Amyotrophic Lateral Sclerosis, on Chromosome 18q Collette K. Hand, Jawad Khoris, François Salachas, François Gros-Louis, Ana.

Hal M. Hoffman, Fred A. Wright, David H. Broide, Alan A

A Missense Mutation in the Zinc-Finger Domain of the Human Hairless Gene Underlies Congenital Atrichia in a Family of Irish Travellers Wasim Ahmad, Alan.

E. Warwick Daw, Simon C. Heath, Ellen M. Wijsman

Localization of a Gene for Duane Retraction Syndrome to Chromosome 2q31 Binoy Appukuttan, Elizabeth Gillanders, Suh-Hang Juo, Diana Freas-Lutz, Sandra.

Linkage Analysis Identifies a Novel Locus for Restless Legs Syndrome on Chromosome 2q in a South Tyrolean Population Isolate Irene Pichler, Fabio Marroni,

Linkage Analysis of X-linked Cone-Rod Dystrophy: Localization to Xp11

Retinitis Pigmentosa and Progressive Sensorineural Hearing Loss Caused by a C12258A Mutation in the Mitochondrial MTTS2 Gene Fiona C. Mansergh, Sophia.

A Severely Affected Male Born into a Rett Syndrome Kindred Supports X-Linked Inheritance and Allows Extension of the Exclusion Map Carolyn Schanen, Uta.

Genomewide Scan in Families with Schizophrenia from the Founder Population of Afrikaners Reveals Evidence for Linkage and Uniparental Disomy on Chromosome.

A Gene Locus Responsible for the Familial Hair Shaft Abnormality Pili Annulati Maps to Chromosome 12q24.32–24.33 Kathrin A. Giehl, Gertrud N. Eckstein,

Mapping of Gene Loci for Nephronophthisis Type 4 and Senior-Løken Syndrome, to Chromosome 1p36 Maria J. Schuermann, Edgar Otto, Achim Becker, Katrin.

A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

Hereditary Isolated Renal Magnesium Loss Maps to Chromosome 11q23

Tracy Dixon-Salazar, Jennifer L. Silhavy, Sarah E. Marsh, Carrie M

A Deleterious Mutation in SAMD9 Causes Normophosphatemic Familial Tumoral Calcinosis Orit Topaz, Margarita Indelman, Ilana Chefetz, Dan Geiger, Aryeh.

Figure SCA10 in a Chinese Han family (A) Pedigree of the Chinese Han spinocerebellar ataxia type 10 (SCA10) family. SCA10 in a Chinese Han family (A) Pedigree.

A New Locus for Autosomal Recessive Hypercholesterolemia Maps to Human Chromosome 15q25-q26 Milco Ciccarese, Adolfo Pacifico, Giancarlo Tonolo, Paolo.

Albena Jordanova, Florian P

A Gene for an Autosomal Dominant Scleroatrophic Syndrome Predisposing to Skin Cancer (Huriez Syndrome) Maps to Chromosome 4q23 Young-Ae Lee, Howard P.

Identification of a New Gene Locus for Adolescent Nephronophthisis, on Chromosome 3q22 in a Large Venezuelan Pedigree Heymut Omran, Carmen Fernandez,

The Gene Encoding Nicastrin, a Major γ-Secretase Component, Modifies Risk for Familial Early-Onset Alzheimer Disease in a Dutch Population-Based Sample

A New Familial Amyotrophic Lateral Sclerosis Locus on Chromosome 16q12

C. Denier, S. Goutagny, P. Labauge, V. Krivosic, M Arnoult, A

Assignment of the Muscle-Eye-Brain Disease Gene to 1p32-p34 by Linkage Analysis and Homozygosity Mapping Bru Cormand, Kristiina Avela, Helena Pihko,

Homozygosity Mapping in Families with Joubert Syndrome Identifies a Locus on Chromosome 9q34.3 and Evidence for Genetic Heterogeneity Kathrin Saar, Lihadh.

A Locus for Autosomal Dominant Hereditary Spastic Ataxia, SAX1,Maps to Chromosome 12p13 I.A. Meijer, C.K. Hand, K.K. Grewal, M.G. Stefanelli, E.J. Ives,

Mapping of a New SGBS Locus to Chromosome Xp22 in a Family with a Severe Form of Simpson-Golabi-Behmel Syndrome L.M. Brzustowicz, S. Farrell, M.B. Khan,

Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts,

Presentation transcript:

Linkage and Association Studies Identify a Novel Locus for Alzheimer Disease at 7q36 in a Dutch Population-Based Sample Rosa Rademakers, Marc Cruts, Kristel Sleegers, Bart Dermaut, Jessie Theuns, Yurii Aulchenko, Stefan Weckx, Tim De Pooter, Marleen Van den Broeck, Ellen Corsmit, Peter De Rijk, Jurgen Del-Favero, John van Swieten, Cornelia M. van Duijn, Christine Van Broeckhoven The American Journal of Human Genetics Volume 77, Issue 4, Pages 643-652 (October 2005) DOI: 10.1086/491749 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family 1270. A blackened symbol represents a patient, and an unblackened symbol represents an unaffected individual or an at-risk individual with unknown phenotype. The Roman numbers to the left of the pedigree denote generations; Arabic numbers above the symbols denote individuals. All numbering is in accordance with that of van Duijn et al. (1994b). The Arabic numbers below the symbols denote age at onset for patients and either age at last examination or age at death for unaffected individuals and at-risk individuals with unknown phenotype. An asterisk (*) indicates an individual who was included in the linkage analysis. The arrow identifies the proband with early-onset AD (age 47 years). The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Brain CT scan of patient III-21 at age 82 years, showing marked cortical and moderate subcortical atrophy, most pronounced in the temporal and frontal regions, with secondary dilatation of the lateral and third ventricles. Mainly frontally localized periventricular leukoencephalomalacia is present as well. The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Genomewide linkage data of the 10-cM density scan of family 1270, with use of the ABI Linkage Mapping Set MD10, version 2, across all chromosomes. Linkage analysis at chromosomes 10, 12, and 21 was performed at a 5-cM density, with use of markers from the ABI Linkage Mapping Set HD-5, version 2. Two-point LOD scores for all markers were calculated using MLINK of the computer package Linkage, version 5.1, and are shown relative to their position on the genetic map (Dib et al. 1996). The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Disguised linkage pedigree of family 1270 (fig. 1). Haplotypes are based on 17 informative markers at 7q36. Haplotypes for individuals from the first and second generations were inferred from genotype data of siblings and offspring. The risk haplotype was arbitrarily set for individual I-2. For confidentiality reasons, haplotypes are shown only for patients; the number of at-risk individuals included in the genotyping are indicated by numbers within diamonds. The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Linkage pedigrees of Dutch families with early-onset AD who share haplotypes at 7q36. Blackened symbols represent patients with AD; unblackened symbols represent unaffected individuals or at-risk individuals with unknown phenotype. Roman numbers to the left of the pedigree denote generations; Arabic numbers above the symbols denote individuals. All numbers are in accordance with those used in the complete pedigrees published by van Duijn et al. (1994b). For patients, the age (in years) at onset is shown below the symbol. An asterisk (*) indicates that DNA was available for genetic analysis. The arrow identifies the proband. To protect privacy of at-risk individuals, the shared haplotypes are shown only for patients. Haplotypes for individual III-20 in family 1242 and individual III-4 in family 1034 were reconstructed from genotype data obtained from their siblings and offspring. For family 1125, only genotype data are given, since segregation data were not informative for deduction of haplotypes. The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 6 Expression analysis of PAXIP1. A, Northern blot of multiple tissues (FirstChoice Human Blot 1 [Ambion]) hybridized with pooled PAXIP1 cDNA fragments C1 (exons 1–9) and C2 (exons 8–22)—obtained by PCR amplification with use of primers C1F (5′-CGCCGCGGAGCCTCCCGGGCCGCCG-3′), C1R (5′-CAGGTGGCCAGCAGTTGCTTATCAGACATC-3′), C2F (5′-GAAGGCTTCTTATTGGGATG-3′), and C2R (5′-TGAAGGAAGCGCAGCAGCTCC-3′)—in a mixture of cDNA (brain, liver, testis, colon, and lymphoblast). B, β-Actin. Transcript lengths (kb) are specified at the left and were calculated on the basis of the Millennium Marker bands marked on the blot. C, RT-PCR of RNA extracted from seven different human brain regions and lymphoblasts of PAXIP1 C-terminal fragment C2 (exons 8–22). Predicted PCR fragment length of C2 is 1,487 bp. The American Journal of Human Genetics 2005 77, 643-652DOI: (10.1086/491749) Copyright © 2005 The American Society of Human Genetics Terms and Conditions