21 Multifactorial Inheritance Flashcards
What does a polygenic trait refer to?
A trait that is the result of many genes
What traits are usually polygenic?
Quantitative traits ie. BP, height and weight
What type of distribution is seen for polygenic traits?
Bell curve, no matter the number of genes and alleles
What other factor is significant for polygenic traits?
Environment
What does the liability distribution model define?
A point on a polygenic distribution curve where a disease state is present. This point is considered the threshold of liability
What is an example of varying threshold of liabilities?
Pyloric stenosis is classic in which the threshold of liability is far lower in males than females
How are recurrent risks derived for multifactorial diseases?
Non mendelian in inheritance, must derive risk from empirical observation and only serves as an estimate
What are the five increasing recurrence risks relative to the proband? (originator of pedigree study)
More than 1 affected family // proband highly affected // proband is of less affected sex // much higher the closer the relationship // risk to siblings and offspring is sqrt of population risk
What are the two contributing factors increasing single gene trait complexity?
Locus heterogeneity and background effects
What are two methods to determine the role of environment vs genetics for a specific trait?
Twin and adoption studies
What are the categorization of twin pairs?
Concodant if both affected and discordant if only one affected
How are twin studies interpreted based on qualitative and quantitative traits?
Concordance rate for qualitative and intraclass correlation for quantitative traits
How is heritability calculated using twin studies?
Heritability is twice the difference between the monozygotic and dizygotic concordance rates
What forms the basis of adoption studies?
Inheritance of a trait in adopted vs biological children and note if occurrence is the same rate = environment
What are phenocopies?
A possibly environmental trait without an associated genetic cause
What are quantitative trait loci?
Areas of the genome where genes associated with a specific polygenic trait are located
How are QTL’s found?
Genome scan>alleles at each loci involved with trait>screen for candidate genes
What is an alternate more cost effective determining method to finding QTLs?
Using siblings with the same disorder as they must share genes causing the effect as well as 50% of genes in general. Optimal if third sibling without disorder can be used.
What are the three most common multifactorial disorders?
Heart disease, hypertension and diabetes
How does family and genetics factor into heart failure?
Positive history, # affected family, affected females, early onset and Hx of familial hypercholesterolemia all contribute to greater risk
What type of disorder is familial hypercholesterolemia and what are some important characteristics?
Autosomal dominant, quantitative trait which presents with double cholesterol, atherosclerosis risk, xanthomas. Homozygotes are much severely affected.
What gene is usually affected in familial hypercholesterolemia?
LDLR gene for the LDL receptor
What are the classes of LDLR mutations from Class I-V
Starting from I = No receptor->degraded/no ER exit->No LDL binding->no migration to cell surface->Cannot unbind LDL/not recycled to surface
Why is decreasing cholesterol and fats only lead to a modest effect on hypercholesterolemia?
Cholesterol can also be synthesized
What is the best Tx for hypercholesterolemia?
Diet to limit intake, bile binders(cholestyramine) to limit scavenging, statins to inhibit synthesis of cholesterol
Other than FH what other cardiac problems are associated with genetics?
half of C. Hypertrophy familial autosomal dominant, ⅓ of Dilated cardiomyopathy mixed/mito dominance, long QT syndrome
What genetic mutations are associated with stroke?
Mito MELAS, dementia causing NOTCH3, Clotting inhibitors protein C/S, Leiden Factor V leading to hypercoagulability
What are the two specific associated genetic syndromes presenting as HTN and what other general mutated pathways can contribute?
Liddle syndrome(ENaC), Gordon Syndrome(WNK2/4) and mutations of the corticosteroid and RAAS
What are the three types of diabetes?
I - early onset, lack of insulin // II - late onset, resistance // MODY - intermediate onset, autosomal dominant
What gene mutations are implicated in diabetes type I and how gene related is it?
HLA DR3/4 and VNTR at 5’ end of insulin gene, 50% concordance
What gene mutations are implicated in diabetes type II and how gene related is it?
Calpain-10 exacerbated by PPAR-g mutations, 97% concordance, risk increased exponentially by poor diet/exercise
What gene mutations are implicated in MODY?
Glucokinase, HNF, IPF and NEUROD1 = all transcription factors responsible for pancreatic development and insulin regulation
What genes are possibly associated with Obesity?
Leptin, neuropeptide Y and MCR4
Why is simply providing leptin to humans usually not effective at reversing obesity?
Most are simply resistant and not deficient
What autosomal dominant disorders can result in Alzheimers?
Gain of function for Presenilis or mutation of APP
