Transcript 掌握相关的疾病基因组学研究技术新进展。

Genetics of Renal Disorders
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: C303, Teaching Building
2015/04
Learning Objectives
• 了解泌尿系统疾病的遗传学研究现状。
• 掌握相关的疾病基因组学研究技术新进
展。
Autosomal dominant polycystic
kidney disease
Thompson &Thompson Genetics in Medicine, 7th Ed
（双语版，2009）
● Clinical Case Studies:
32. Polycystic Kidney Disease
● Pages 355
Recommended Reading:
Qi X-P, …, Zhang X-N*. Genetic diagnosis of
autosomal dominant polycystic kidney disease by
targeted capture and next-generation sequencing:
utility and limitations. Gene, 2013; 516(1):93-100.
Recommended Reading
1. Wuttke M, et al. Genome-wide association
studies in nephrology: using known
associations for data checks. Am J Kidney
Dis 2015;65(2):217-22.
2. Xu X, et al. Single-cell exome sequencing
reveals single-nucleotide mutation
characteristics of a kidney tumor. Cell
2012;148(5):886-895.
Introduction
• Kidney diseases pose a significant global
disease burden
• The most common form, chronic kidney
disease (CKD), affects an estimated 10% of
adults in many countries and the prevalence
is increasing
• Over 250 syndromes and monogenic
disorders have been reported to have an
increased risk for congenital anomalies of
the kidney and urinary tract (CAKUT)
The role of a genetic contribution
to kidney disease is supported by
• The presence of monogenic diseases with
renal manifestations
• Heritability studies of kidney function
measures
• Familial aggregation studies of complex
kidney diseases
Heritability studies of kidney
function measures
• Heritability estimates for the most
commonly used measure of kidney
function, GFR (肾小球滤过率), range
from 0.33 to 0.82, indicating that 33%82% of the interindividual variation in
GFR estimates in these studies could be
explained by additive genetic effects.
Familial aggregation studies of
complex kidney diseases
• Familial aggregation studies show that
end-stage renal disease (ESRD) and
earlier stages of CKD cluster in families.
The presence of monogenic
diseases with renal manifestations
• Autosomal dominant polycystic kidney
disease (ADPKD)
• The most common form of PKD with an
estimated incidence of approximately 1/400
to 1/1 000 individuals worldwide. It roughly
accounts for 10% of patients with chronic
renal failure requiring hemodialysis (血液透
析) or transplantation.
Autosomal dominant PKD (ADPKD)
• PKD1 (16p13.3), 46 exons, accounting for ~85% of
affected individuals
• PKD2 (4q21-q23): 15 exons, ~15%
Distribution of PKD1 mutations identified
in Thai patients with ADPKD →Polycystin
ADPKD Database, PKDB：
http://pkdb.mayo.edu
• PKD1：已发现了436种突变 。
• PKD2：已发现了115种突变 。
• The 5’ 2/3 of PKD1 (exons 1–32) is duplicated
six times on chromosome 16 within 6
pseudogenes (PKD1 P1-P6). The PKD1 P1-P6
pseudogenes share a 97.7% sequence identity
with the genuine PKD1, although they carry
some large deletions compared with the
genuine PKD1.
Genome-wide association studies
(GWAS)
• GWAS test for association, or linkage
disequilibrium, between a disease and a marker
(or several markers) by testing many thousands of
markers across the genome.
• Typically this is accomplished with microarray
analysis of disease cases and unaffected controls.
• As in all case-control studies, considerable care
must be taken to avoid spurious results by closely
matching cases and controls.
Linkage:
Genes on the
same cs are
linked if they
are
transmitted
together in
meiosis more
frequently
than chance
would allow.
Linkage disequilibrium (LD)
• The occurrence together of 2 or more
alleles at closely linked loci more
frequently than would be expected by
chance.
• D’: 0（no LD）~±1 (complete
association)
Association
• A tendency of two characters (diseases,
marker alleles, etc.) to occur together at
non-random frequencies.
• Association is a simple statistical
observation, not a genetic
phenomenon, but can sometimes be
caused by linkage disequilibrium.
IgA肾病是最常见的原发性肾小球肾炎，也是引起终末期肾脏疾
病的一个重要原因。
Cell, 2012;148(5):886-895