1. Genetics of Kidney Diseases 张咸宁 zhangxianning@zju.edu.cn Tel ： 13105819271; 88208367 Office: A705, Research Building 2013/04

2. 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。

3. Autosomal dominant polycystic kidney disease Thompson &Thompson Genetics in Medicine, 7 th Ed （双语版， 2009 ） ● Clinical Case Studies: 32. Polycystic Kidney Disease ● Pages 355 Recommended Reading: Rossetti S, et al. Identification of Gene Mutations in Autosomal Dominant Polycystic Kidney Disease through Targeted Resequencing. J Am Soc Nephrol, 2012; 23:915–933.

4. Recommended Reading 1.Yu XQ, et al. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet, 2011;44(2):178-182. 2.Xu X, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell, 2012;148(5):886-895.

6. 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.

7. 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

8. Heritability studies of kidney function measures Heritability estimates for the most commonly used measure of kidney function, GFR, 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.

9. 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.

11. 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 or transplantation.

12. Autosomal dominant PKD (ADPKD) PKD1 (16p13.3), accounting for ~85% of affected individuals PKD2 (4q21-q23): ~15%

13. Distribution of PKD1 mutations identified in Thai patients with ADPKD → Polycystin

15. 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.

18. 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.

19. Linkage: Genes on the same cs are linked if they are transmitted together in meiosis more frequently than chance would allow.

20. 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)

21. 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.

30. 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。

31. Cell, 2012;148(5):886-895