single nucleotide assosiation mdd.pptx
- 2. Title:- SNP and Halophyte analysis of Noval Tryptophan hydroxylase isoform (TPH) gene provides evidence for association with MDD Journal: Molecular Psychiatry (2004) Author: P Zill, TC Baghai, P Zwanzger, C Schu¨ le, D Eser, R Rupprecht, H-J Mo¨ ller, B Bondy and M Ackenheil Lab: Psychiatric Hospital of the Ludwig- Maximilians-University, Munich, Munich, Germany
- 3. Cohort Size 300 people with major depression (114 males, 186 females) 265 healthy people (138 males, 127 females)
- 4. Role of TPH • Tryptophan hydroxylase is the rate-limiting enzyme that is responsible for the synthesis of serotonin • That is the key neurotransmitter that TPH controls. • In this paper, 2 isoforms of the TPH gene are studied A) TPH1- mRNA is primarily found in peripheral tissues such as the heart, lung, kidney, duodenum, liver, and adrenal gland • Located on chromosome 11p15.3–p16 B) TPH2 - predominantly expressed in the human brain, especially in brain regions like the frontal cortex, thalamus, hippocampus, hypothalamus, amygdala, and most notably, the brain stem, which is the major locus of serotonin-producing neurons • Located on chromosome 12q15,
- 5. Methods used for SNP Study For the genotyping, the SNaPshot technique is employed, which is widely used in the commercial sector. Statistics: Hardy–Weinberg, permutation tests, haplotype frequency, LD 10 SNPs were selected in the TPH2 gene, between 5-7 exons
- 6. Key Finding • SNP rs1386494 showed a statistically significant association with major depression (p=0.0012, remaining significant after correction with p=0.012). • The G-allele of rs1386494 was more frequent in depressed patients vs. controls. • SNP rs1843809 showed a marginal association (p=0.0496), but it was not significant after correction.
- 7. Haplotype Analysis • Three main haplotypes were identified, collectively representing 85% of all combinations in patients and 90% in controls. • Global P-value for haplotype association with MD: 0.0001 (highly significant). • Haplotype 3 (CGGCAATGAT): Twice as frequent in controls as in patients (16% vs. 8%), suggesting a possible protective role. • Haplotypes 4 and 5: Found only in depressed patients (5% and 4%, respectively), suggesting they may increase risk for depression.
- 8. Linkage Disequilibrium (LD) Analysis: • The LD pattern was pretty similar in both the patient and control groups, suggesting that they were almost identical. • Most of the 10 SNPs we looked at were closely linked and had a strong correlation with each other. This means they tend to be inherited together in blocks. • But there were some exceptions. For instance, SNP A (rs1386488) had weaker LD with other SNPs. • Specifically, there was no LD between SNP A (rs1386488) and SNP G (rs1386493), and between SNP A (rs1386488) and SNP J (rs4760815) in the depressed patient sample. • Similarly, in the control sample, there was also no LD between SNP A (rs1386488) and SNP J (rs4760815), and between SNP E (rs1386494) and SNP J (rs4760815).
- 9. Major Discussion Points First strong evidence that TPH2 gene variants (especially rs1386494 and certain haplotypes) are associated with major depression. Suggests a “duality” in the serotonergic system: TPH1 is active in peripheral tissues, while TPH2 is predominant in the brain and may be more relevant to psychiatric conditions. Large blocks of SNPs are inherited together, but the significant association was mainly localized in the rs1386494 and specific haplotypes.