n on -m endelian i nheritance and t he complex genetics of common disorders h uman g enetics g...
TRANSCRIPT
![Page 1: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/1.jpg)
NON-MENDELIAN INHERITANCE AND THE COMPLEX
GENETICS OF COMMON DISORDERS HUMAN GENETICS
GENETICS 202
Jon BernsteinDepartment of Pediatrics
October 8, 2015
![Page 2: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/2.jpg)
Session Goals – Non-Mendelian Inheritance
Understand how imprinting occurs and gain familiarity with conditions in which imprinting plays a role.
Understand the nature of mitochondrial inheritance and its implications for clinical manifestation of mitochondrial disease and risk of familial recurrence.
![Page 3: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/3.jpg)
Session Goals – Multifactorial traits Understand the concepts of multifactorial inheritance and heritability.
Understand what epidemiological evidence can be used to support the existence of a genetic component to the etiology of a particular trait◦ Family studies◦ Twin studies
Understand how recurrence risks for complex or multifactorial traits are estimated
![Page 4: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/4.jpg)
Lecture Outline – Non-MendelianNon-Mendelian inheritance◦ Imprinting/Epigenetic Disorders
Clinical Case Mechanisms
Deletions Uniparental disomy Imprinting center deletions Epimutations
Recurrence risk counseling
◦Mitochondrial inheritance Clinical case
Heteroplasmy Recurrence risk counseling
![Page 5: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/5.jpg)
Clinical Case - ImprintingA newborn infant with low
muscle tone has a cytogenetic test done which shows a deletion of chromosome 15 at q11.2-q13.
What condition does this infant have?
Sahoo et al., Eur J Hum Genet, 2007
![Page 6: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/6.jpg)
Clinical Case - Imprinting
Deletion on chromosome at 15q11-13◦Prader-Willi syndrome
Loss of paternal contribution◦Angelman syndrome
Loss of maternal contribution
![Page 7: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/7.jpg)
http://www.pwsausa.org
Prader-Willi Syndrome
•Hypotonia and feeding difficulties in early infancy•Later excessive eating and gradual development of obesity•Motor and language delay•Hypogonadism
![Page 8: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/8.jpg)
http://www.genereviews.org
Angelman Syndrome
•Hypotonia, poor feeding•Microcephaly (acquired)•Seizures• Absent or severely limited speech•Ataxia•Inappropriately happy demeanor
![Page 9: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/9.jpg)
Kumar: Robbins and Cotran Pathologic Basis of Disease, Professional Edition , 8th ed. via MDConsult.com
An infant with a 15q11.2-q13 microdeletion
![Page 10: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/10.jpg)
Normal Gene Expression at 15q11.2-q13
![Page 11: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/11.jpg)
Genomic ImprintingResults in genes that show different expression
dependent upon the parent they are inherited from◦Parent of origin effect
These genes are imprinted with a distinguishing molecular message as they pass through meiosis in either the egg or sperm
![Page 12: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/12.jpg)
Epigenesis – the establishment of imprints Involves DNA methylation
Imprints largely persists through DNA replication and cell division throughout life but is removed during gametogenesis and then re-established according to the sex of the transmitting parent
Patterns can be tissue specificThe New Genetics, nigms.nih.gov
![Page 13: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/13.jpg)
Imprinted Regions in the Human Genome
Regions of chromosomes 6, 7, 11, 14, 15 and others◦Catalog at University of Otago in New Zealand
http://igc.otago.ac.nz/home.html
![Page 14: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/14.jpg)
Uniparental Disomy
Both members of a pair of homologous chromosomes originated in the same parent◦Heterodisomy◦ Isodisomy
Delaney et al., Current Protocols in Human Genetics, 2008
![Page 15: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/15.jpg)
Trisomy Rescue
Thought to be responsible for most cases of uniparental heterodisomy
www.genereviews.org
![Page 16: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/16.jpg)
Synthesis Question
Which would be associated with an increased risk of Prader-Willi Syndrome◦A) Maternally derived isochromosome 15◦B) Paternally derived isochromosome 15◦C) Maternally derived ring chromsome 15◦D) Paternally derived ring chromosome 15
![Page 17: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/17.jpg)
Angelman Syndrome - Mechanism
http://www.genereviews.org
UBE3A encodes a ubiquitin ligase◦ May be important in appropriate degradation of proteins involved in
synaptogenesis
![Page 18: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/18.jpg)
Prader-Willi Syndrome - Mechanism
Prader-Willi syndrome◦ HBII-85 snoRNA cluster
Deletion, Sahoo, 2008, Nat Genetics, PMID: 18500341
◦ MAGEL2 Gene Schaaf et al., Nat Genet. 2013 Nov;45(11):1405-8. PMID: 24076603
http://www.genereviews.org
![Page 19: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/19.jpg)
Mechanisms for loss of expression of a parental contribution in an imprinted region
MicrodeletionBoth chromosomes come from one parent◦ Uniparental disomy
EpimutationImprinting center mutation
Other causes – mutation of regulated genes◦ UBE3A mutation (Angelman)◦ Deletion of HBII-85 snoRNA cluster (Prader-Willi)
![Page 20: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/20.jpg)
http://herkules.oulu.fi/isbn9514270274/html/x838.html
Genetic changes of chromosome region 15q11-q13 in Prader-Willi and Angelman syndromes in Finland, Dissertation of Hannaleena Kokkonen, 2003
Summary of Mechanisms for Prader-Willi and Angelman Syndromes
Normal Prader-Will
Angelman
![Page 21: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/21.jpg)
Angelman Syndrome – Recurrence Risk
Risk of recurrence in siblings depends on mechanism◦ Very low risk of recurrence for typical deletions◦ Risk can be up to 50% for UBE3A mutations or imprinting
center deletions
![Page 22: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/22.jpg)
Prader-Willi Syndrome – Recurrence Risk
Risk of recurrence in siblings depends on mechanism◦ Very low risk of recurrence for typical deletions◦ Risk can be up to 50% for imprinting center deletions
![Page 23: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/23.jpg)
Detecting DNA Methylation
Genetic changes of chromosome region 15q11-q13 in Prader-Willi and Angelman syndromes in Finland, Dissertation of Hannaleena Kokkonen, 2003
http://www.genereviews.org
SNRPN Methylation Study
![Page 24: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/24.jpg)
Methylation testing – Prader Willi
Detects 99% of cases◦Deletion, UPD, Imprinting Center Defect or
Epimutation◦Yield is lower for Angelman as UBE3A mutation cases
have normal methylation
![Page 25: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/25.jpg)
Follow-up to an abnormal methylation study
FISH or CGH to look for a large deletionUniparental disomy studiesImprinting center studies
What if none of the above are positive?
![Page 26: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/26.jpg)
Prader-Willi and Angelman Syndrome
A good portion of Genetics 202 to date in a nutshell◦Large deletions◦Point mutations◦Epimutations◦ Imprinting center deletions◦Uniparental disomy
![Page 27: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/27.jpg)
Clinical Case – Mitochondrial Inheritance
A 30 year old male develops progressive bilateral vision loss over the course of several months. A family history is obtained.
![Page 28: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/28.jpg)
Clinical Case – Familial Blindness
Thompson & Thompson: Genetics in Medicine, 2007
A condition called Leber’s Hereditary Optic Neuropathy is segregating in this family.
What is the evidence for mitochondrial inheritance?
What is the risk of recurrence in offspring for the individual marked by the arrow?
![Page 29: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/29.jpg)
Mitochondrial DNA
Small circular DNA16.5 kb37 genes encoding◦Ribosomal RNAs◦Transfer RNAs◦13 subunits of the oxidative phosphorylation system
Kumar and Fox, British Journal of Cancer (1974) 29, 447–461, PMID: 4368398
![Page 30: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/30.jpg)
Inheritance of Mitochondrial DNA
Mitochondria are almost exclusively transmitted from the mother
Each ovum contains ~100,000 mitochondriaEach sperm contains less than 100 and these
appear to be eliminated soon after fertilization
![Page 31: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/31.jpg)
Mitochondrial DNA Mutations and Heteroplasmy
An individual cell may contain some mtDNA molecules that have a mutation and other molecules do not
This proportion may change as cells divide and mitochondria proliferate
Generally, the larger the percentage of mutant mtDNA molecules, the more severe the expression of the disease
![Page 32: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/32.jpg)
The mtDNA Bottleneck
Nature Reviews Genetics 6, 389-402 (May 2005)
![Page 33: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/33.jpg)
Post-zygotic changes in heteroplasmy
![Page 34: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/34.jpg)
Not all mitochondrial disease shows mitochondrial inheritance
The majority of the subunits of the respiratory chain complexes are nuclearly encoded.
Some mitochondrial diseases commonly result from post-zygotic mutations.◦mtDNA deletion syndromes
An Introduction to Genetic Analysis, 7th edition, 2000
![Page 35: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/35.jpg)
Mitochondrial Inheritance – Key PointsNo offspring of males will be affected.
All offspring of females are at risk to be affected, however, severity cannot be predicted because of heteroplasmy.
Not all mitochondrial disease shows mitochondrial inheritance.
![Page 36: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/36.jpg)
Lecture Outline – Complex traits
Multifactorial versus environmental versus Mendelian traitsClinical Case – Bipolar disease◦Building a case for a multifactorial etiology
Family studies Twin studies
Heritability
◦Estimating recurrence risk for a multifactorial traitThe polygenic threshold model for multifactorial inheritance
![Page 37: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/37.jpg)
What do these conditions have in common?
Down syndrome, 22q11 deletion syndrome, Fragile X syndrome, ARPKD, Duchenne muscular dystrophy, LHON◦Clinical features can be almost entirely explained by a
single genetic event◦Relatively high or complete penetrance
![Page 38: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/38.jpg)
Conditions that often do not share the features of single genetic cause, high penetrance
High blood pressureHigh cholesterolDiabetes MellitusAlzheimer’s diseaseBipolar diseaseAutismMany forms of cancer
These are multifactorial conditions
Relatively common Relatively low familial
recurrence risks Often have a well understood
environmental component
Can these traits ever be Mendelian?
![Page 39: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/39.jpg)
Multifactorial versus single gene versus environmental causes
New Clinical Genetics 2eAndrew Read and Dian DonnaiISBN: 9781904842804© Scion Publishing Ltd, 2011
![Page 40: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/40.jpg)
Clinical Case
Your patient and her paternal great uncle through her grandfather have a diagnosis of bipolar disorder.
What is the predicted risk of recurrence in offspring of your patient?
![Page 41: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/41.jpg)
Clinical Case – What do we need to know to estimate recurrence risk?
Is the condition genetic?◦What is the mode of inheritance?
![Page 42: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/42.jpg)
What if the inheritance of bipolar disorder were unknown?
Building a case for Multifactorial (Complex) Inheritance◦ Familial aggregation
Evidence for a genetic component to etiology, not solely environmental
◦ Does not display Mendelian inheritance Relatively low recurrence risk
![Page 43: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/43.jpg)
Identifying a multifactorial disorder – showing familial aggregation
Family studies◦ Identifying families in which at least one individual
has a particular disorder◦Study the incidence of the disorder in other family
members in comparison to control subjects
![Page 44: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/44.jpg)
Is there familial aggregation in bipolar disease?Condition Relative risk for siblings of an
affected individual vs general population
Bipolar Disorder 7-10x
Coronary artery disease 2-7x
Crohn’s Disease 17-35x
Hypertension 2.5-3.5x
Rheumatoid Arthritis 5-10x
Type 1 Diabetes 15x
Type 2 Diabetes 3x
![Page 45: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/45.jpg)
Family Studies: CaveatsDo family studies clearly discriminate between genetic and
environmental factors?◦ Families have shared environmental factors
Diet Toxins Parenting methods Education
◦Risk of ascertainment bias Genetics and other specialty clinics may attract families with multiple
affected members
![Page 46: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/46.jpg)
Identifying a multifactorial disorder – Quantifying the genetic contribution to a trait -- Heritability
http://homepages.strath.ac.uk/~dfs99109/BB310/MGlect5.html
Fraction of total phenotypic variance of a trait that is caused by genes◦ The higher the heritability,
the greater the contribution of genes to the trait H2=0, genes contribute nothing H2=1, genes are totally
responsible for the trait
H2=Genetic variance / Total variance
In concept one estimates heritability by changing genotypes while holding the environment constant
![Page 47: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/47.jpg)
Using Twin Studies to Measure HeritabilityCompare disease/trait frequency or severity in
Monzygotic and Dizygotic twins◦ Twins have a similar environment
◦ Twins share defined amounts of genetic material Monozygotic (MZ)
Arise from a single fertilized zygote which splits in two Genetically identical 1/3 of all twins
Dizygotic (DZ) Two ova are fertilized by different sperm Genetically siblings (fraternal) – Share ½ of genetic information 2/3 of all twins
![Page 48: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/48.jpg)
Interpreting Twin StudiesDisease concordance less than
100% in MZ twins or 100% in DZ twins◦ Nongenetic factors play a role in
the disease.A large difference in
concordance between MZ vs. DZ twins◦ Supports a genetic component to
the etiology for a disease.
Concordant twins◦Both are affected (with
bipolar disorder)Discordant twins◦Only one of the pair is
affected (with bipolar disorder)
![Page 49: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/49.jpg)
Heritability for a dichotomous trait (approximation)
% MZ concordance - % DZ concordance 100% - % DZ concordance
Dichotomous trait – Definition: A trait that one has or does not have.
Do MZ twins and DZ twins have environments that are similar to the same degree?
sciencephoto.com
![Page 50: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/50.jpg)
Overcoming the effects of shared environment in a twin study
Study twins reared apart◦Should minimize the effect of shared environment
◦Limitations/Challenges Difficult to find large numbers of twins reared apart Possibly selects for twins who have been in contact as may
be more likely to participate Intrauterine environment still shared
![Page 51: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/51.jpg)
What do twin studies show for bipolar disease?
DisorderCleft lipType 1 diabetesSchizophreniaBipolar disease
Concordance (%) h2
MZ DZ30 2 29%40 5 37%46 15 36%62 8 59%
![Page 52: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/52.jpg)
Evidence that bipolar disease is multifactorial
Shows familial aggregationShows evidence of heritability in twin studies
![Page 53: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/53.jpg)
Clinical Case Your patient and her paternal
great uncle through her grandfather have a diagnosis of bipolar disorder.
What is the predicted risk of recurrence in offspring of your patient?◦ Inheritance appears
multifactorial
![Page 54: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/54.jpg)
Recurrence Risks for Multifactorial Conditions
Risks are not directly estimated by calculation as is commonly done for Mendelian disorders◦Are empirically estimated◦Generally are smaller than for Mendelian disorders
![Page 55: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/55.jpg)
Clinical Case: Empiric Risks for Bipolar Disorder
Relationship to index caseSibParentSib and one parentBoth parentsSecond-degree relativeMonozygotic twinDizygotic twinFirst cousinGeneral population
Risk (%)13152050570202-32-3
![Page 56: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/56.jpg)
![Page 57: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/57.jpg)
New Clinical Genetics 2eAndrew Read and Dian DonnaiISBN: 9781904842804© Scion Publishing Ltd, 2011
Falconer’s Polygenic Threshold Model
How do the effects of multiple genes combine to determine susceptibility to a disease?A different environment might move the threshold.
![Page 58: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/58.jpg)
Multifactorial Inheritance: Factors that Increase Risk to RelativesCloseness of relationship to
affected family member(s)Multiple affected family
membersSevere or early-onset disease
in affected family member(s)
Salt intake is an environmental risk factor for hypertension – how would this be represented in the threshold model?
“Genetic Load”
![Page 59: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/59.jpg)
Lecture Summary – Non-Mendelian Inheritance
Imprinting disorders◦Prader-Willi and Angelman Syndrome
Mechanisms Recurrence risk Molecular Testing
Mitochondrial inheritance
![Page 60: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/60.jpg)
Lecture Summary – Complex traits
Multifactorial traits occur as the result of a combination of genetic and environmental factors◦Threshold model
Heritability can be considered as the fraction of variance in a trait in a population attributable to genetic variance
![Page 61: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/61.jpg)
Summary of Methods for Demonstrating a Genetic Contribution to Complex Traits
New Clinical Genetics 2eAndrew Read and Dian DonnaiISBN: 9781904842804© Scion Publishing Ltd, 2011
Estimates of recurrence risk for multifactorial traits are based on empiric data
![Page 62: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/62.jpg)
Review Question
An abnormal methylation pattern is seen in Angelman syndrome due to◦A) Uniparental disomy◦B) Microdeletion◦C) Epimutation◦D)UBE3A point mutation
![Page 63: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/63.jpg)
Review Question
Heteroplasmy can result in◦A) Variable expressivity◦B) Abnormal imprinting◦C) Uniparental disomy◦D) Autosomal recessive inheritance when a nuclear
gene is involved
![Page 64: N ON -M ENDELIAN I NHERITANCE AND T HE COMPLEX GENETICS OF COMMON DISORDERS H UMAN G ENETICS G ENETICS 202 Jon Bernstein Department of Pediatrics October](https://reader035.vdocuments.us/reader035/viewer/2022081513/5697bfdd1a28abf838cb160e/html5/thumbnails/64.jpg)
Review QuestionA potential bias in twin studies is?◦A) Monozygotic twins share more genetic information than
dizygotic twins◦B) Monozygotic twins tend to have more similar environments
than dizygotic twins◦C) Dizygotic twins tend to have more similar environments
than monozygotic twins◦D) Dizygotic twinning is more heritable than monozygotic
twinning