The analysis of A Genome-wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1 Rodney Knowlton Kyle Andrews

“The Annals of Human Genetics is an international journal, publishing rigorously peer-reviewed research.” Received: 16 March 2009 Accepted: 26 March 2009?

Interaction between Fibrinogen and IL-6 Genetic Variants and Associations with Cardiovascular Disease Risk in the Cardiovascular Health Study Received: 2 March 2009 Accepted: 11 September 2009 Received: 1 July 2009 Accepted: 28 October 2009 Linkage Disequilibrium Pattern in Asthma Candidate Genes from 5q31-q33 in the Singapore Chinese Population Received: 12 August 2009 Accepted: 7 January 2010 GJB2 Mutations in Mongolia: Complex Alleles, Low Frequency, and Reduced Fitness of the Deaf 6 months 3 months 5 months

Annals of Human Genetics Tier ? Audience? Editor: Andres Ruiz-Linares Established 1925 Changed title from “Eugenics” in 1956 Tier 2 Narrowed to Human Geneticist

Deqiong MaMargaret A. Pericak-Vance Based out of Miami Institute for Human Genomics Only paper without experimental cause and effect, rather deals with association

Genome-wide Association Study Examine Genetic Variations w/ Disease Primarily used for complex diseases – environmental and genetic Heart Disease, Obesity, other non-Mendelian

Autism Neurodevelopmental Disorder 1 out of 110 children are diagnosed – More prevalent in males: 1 in 70. Diagnosed between 18 months and 24 months

Diagnostic Difficulties Classified as a spectrum disorder Diagnosis is Difficult – Devolopmental Behavior – Social Interaction Arbitrary Guidelines Difficult to Pinpoint Why would Autism be a difficult disease to work with diagnostically?

Autism (study definition) Operationally Define Autism Ages between 3 and 21 yrs Clinical Diagnosis Expert Diagnosis – DSM-IV* – ADI-R – Review Panel Developmental level of 18 months

Other considerations Excluded severe sensory problems – Visual or hearing Significant motor impairments – Fail to sit at 12 months or walk at 24 months Other Disorders

Origins of Autism? Genetic Link – Twin + Sibling Studies Two Hypotheses 1)Rare Mutation 2)Common Variant What types of individuals would be utilized in determining genetic link to autism?

Polymorphisms DNA sequence variation that common in population What is the difference between a mutation and polymorphism? A mutation is a change in a DNA sequence that is rare in the population

Single Nucleotide Polymorphisms SNP’s – Single Nucleotide Polymorphisms Linkage Disequilibrium – Non-random Association

Genetic Variations & Diseases Common Genetic Variations Even Coverage across Genome Allows Markers for Mapping

SNP Detection

Micro-Array Isolate mRNA Label cDNA Oligonucletides on Plate Detection of Color Ratios

Infinium II® Bead Chip Assay All Processes are Automated using Tecan EVO Isolate Genomic DNA from White Blood Standardized Amounts with Gel Electrophoresis Genotype with Bead Assay

Only DNA Specific SNP Probe Extend 1 Base Pair Attach Fluorescent Nucleotide Determines SNP Genotype

Call Rates and Ambiguity Color threshold determined by computer – Call Threshold Determines genotype for each individual Variability Misidentification