Multifactorial Inheritance

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Allele

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One of the alternative versions of a gene or DNA sequence at a given locus.

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genotype

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The genetic constitution of an individual, as distinguished from the phenotype. The alleles present at one locus.

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Genome-Wide Association study (GWAS)

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A case-control study in which genetic variation, often measured as SNP genotypes, is compared between people with a particular trait and unaffected individuals.

-GWAS have provided a wealth of information concerning the role that common genetic variants play in human disease. These studies address the central hypothesis that common genetic variation, perhaps in
association with environmental factors, is responsible for common human disease.

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Haplotype

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A set of DNA variations, or polymorphisms, that tend to be inherited together. A haplotype can refer to a combination of alleles or to a set of single nucleotide
polymorphisms (SNPs) found on the same chromosome.

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Linkage Disequilibrium

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In a population, co-occurrence of a specific DNA marker and a disease at a higher frequency than would be predicted by random chance.

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Locus

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The position occupied by a gene on a chromosome. Different forms of the gene (alleles) may occupy the locus.

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Multifactorial Inheritance

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The type of non-Mendelian inheritance shown by traits that are determined by a combination of multiple factors, genetic, and environmental. It is also
termed complex inheritance. In principle, multifactorial inheritance can be polygenic
(involving many genes at different loci), but it always has to be influenced by the environment.

-The risk factors for common diseases are
dependent on a combination of genetic and environmental factors. You are responsible for recognizing what a relative risk ratio means, but will not be asked to calculate them for exam items arising from this
lecture. ‘Heritability’ provides a statistical measure that summarizes how much of the variation in a trait in a population is due to variation in genetic factors.

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Polygenic inheritance

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Inheritance determined by many genes at different loci, with small additive effects; not to be confused with multifactorial inheritance, in which environmental
as well as genetic factors may be involved.

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Overview of inheritance

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Historically, much is known about the genetics of
disorders caused by chromosomal abnormalities and single genes. Nevertheless, complex traits and disorders are far more frequent in human populations. They display non- Mendelian inheritance patterns and family aggregation. There are significant differences in the relative population prevalence of diseases associated with chromosome abnormalities
(about 4 per 1000), single gene mutations (about 20 per 1000), and multifactorial inheritance (about 600 per 1000).

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What does information about the Haplotype provide?

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First, it reduces the number of SNPs that need to be genotyped in the human genome since the genotype of one SNP on a haplotype provides information about the genotype of other SNPs on the same haplotype. Also, if one finds an association between the genotype
status of a given SNP and a trait of interest, one cannot assume that given SNP itself is functionally relevant. That is, perhaps a different genetic variant on the same haplotype is functionally relevant. In summary, association does not always mean functional relevance!

-Currently, very robust genotyping technologies exist based on microarray technology. The genotyping technologies provided by Affymetrix and Illumina have provided the backbone for data collection in GWAS and can assign the genotype status of millions of human SNPs in a rapid and cost-effective manner.

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Basic statistics

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A key point to remember is that a statistically significant genetic association does not reflect
on effect size. The magnitude of the effect is often summarized by an Odds Ratio. On slides 23-29, you are provided information for calculating a disease odds ratio. You will be expected to be able to perform this calculation and the formula will not be provided to you. That is, simply memorize the formula, which is pretty intuitive. Once you do that, such calculations are as easy as pie, or 3.14 as provided on Slide 29.

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Age-related Macular Degeneration

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AMD is a common vision disorder that affects the function of the macula, a region near the center of the
retina where visual perception is most acute. It is one of the few examples of ac ommon human disease where commonvariation represents a major risk factor.Protective alleles are observed as well. In
fact, about 70% of the genetic risk can beinferred based on SNP genotypes andsmoking status. These genes highlight therole of inflammation in disease. While commercial gentic tests for AMD risk factor alleles exist, please note that the American Academy of Opthamology provided a press relase in November 2012 stating that at this time its member eye physicians and surgeons should avoid genetic testing for complex eye disorders such as age-related macular degeneration. The organization discourages patients from undergoing such testing until treatment or surveillance strategies can be shown to be of benefit to individuals with specific disease-associated genotypes

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APOE Gene Polymorphisms

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associated with risk of developing AD. In particular, the APOE epsilon 4 (APOE 􀁈4) allele is a significant risk factor that in the homozygous state imparts up to a 12-fold increased life-time risk of developing AD. Note that this risk varies among populations and that <5% of the US population is homozygous for the APOE 􀁈4
allele. While being heterozygous for the APOE 􀁈4 alleles does increase one’s risk of developing AD, it is important to know that well over 50% of APOE 􀁈4 heterozygotes never develop disease. In fact some (quoting Thompson and Thompson) have stated that testing of asymptomatic people for the APOE 􀁈 4 allele remain inadvisable because knowing that one if a heterozygote or homozygote does not mean one will develop AS. One of the reasons is that there is no intervention currently known that can affect the chance one will or will not develop AD.

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Alzheimer Disease (AD)

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AD is the most common cause of dementia among people 65 years of age and older. It currently affects an estimated 5.4 million Americas and the numbers are expected to increase due to the aging US population. AD has intriguing modes of inheritance, as depicted on the right (red depicts early onset familial cases). Familial AD has an autosomal dominant mode
of inheritance and three classic risk factor genes have been identified that have made an enormous impact on our understanding of pathogenic mechanisms.

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AD and Down Syndrome

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This provides an intriguing example of the inter-relationship between two seeming disparate medical conditions. People with Down syndrome develop amyloid plaques and neurofibrillary tangles by age 30 and from 40-70 years of age, 75% of patients develop dementia. Intriguingly, people with AD have three
copies of the APP gene, which is a familial AD gene. Further evidence that APP gene copy number plays a role in Down Syndrome is provided by the observation of an elderly adult with Down syndrome who had a microdeletion resulting in APP disomy and did not develop dementia or classic AD neuropathology.

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Autism Spectrum Disorders

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ASD is an increasingly common disorder diagnosed in children. ASD is an umbrella term that encompasses a group of heterogeneous disorders that have a diverse group of genetic risk factors. Rett syndrome is the only autism spectrum disorder with a known cause. GWAS studies have concluded that common variants affect the risk for ASD but their individual effects are modest. This has lead to the exploration of de novo mutations in disease. As discussed in the “Human
Genome Projects” lecture, de novo mutations increase with paternal age. De novo mutations may account for about 1% of sporadic ASD cases. Many of these mutations occur in genes that have related functions, which points to common pathogenic mechanisms of disease.The data is consistent with oligogenic model where de novo mutations and rare variants contribute to genetic risk. Copy number variants (CNVs) play important roles in autism and other complex diseases. Autism and other disorders have hundreds of relev. gene loci

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Overview of genetic risk factors

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The figure highlights the relationship of risk
allele frequency and genetic effect sizes. In rare Mendelian disorders (such as cystic fibrosis and hereditary breast and ovarian cancer), low frequency alleles can have large effect sizes. In contrast, the common alleles associated with the majority of common disorders (such as autism and Type 2 Diabetes – as to be discussed on Monday) almost
always show small effect sizes. Some notable exceptions include age-related macular degeneration, AD, and Type 1 Diabetes for which certain common alleles can confer a high risk of disease.