Interaction between childhood maltreatment on immunogenetic risk in depression: Discovery and replication in clinical case-control samples.

Major depressive disorder (MDD) is a prevalent disorder with moderate heritability. Both MDD and interpersonal adversity, including childhood maltreatment, have been consistently associated with elevated inflammatory markers. We investigated interaction between exposure to childhood maltreatment and extensive genetic variation within the inflammation pathway (CRP, IL1b, IL-6, IL11, TNF, TNFR1, and TNFR2) in relation to depression diagnosis. The discovery RADIANT sample included 262 cases with recurrent DSM-IV/ICD-10 MDD, and 288 unaffected controls. The replication Münster cohort included 277 cases with DSM-IV MDD, and 316 unaffected controls. We identified twenty-five single nucleotide polymorphisms (SNPs) following multiple testing correction that interacted with childhood maltreatment to predict depression in the discovery cohort. Seven SNPs representing independent signals (rs1818879, rs1041981, rs4149576, rs616645, rs17882988, rs1061622, and rs3093077) were taken forward for replication. Meta-analyses of the two samples presented evidence for interaction with rs1818879 (IL6) (RD=0.059, SE=0.016, p<0.001), with the replication Münster sample approaching statistical significance in analyses restricted to recurrent MDD and controls following correction for multiple testing (q=0.066). The CRP locus (rs3093077) showed a similar level of evidence for interaction in the meta-analysis (RD=0.092, SE=0.029, p=0.002), but less compelling evidence in the replication sample alone (recurrent MDD q=0.198; all MDD q=0.126). Here we present evidence suggestive of interaction with childhood maltreatment for novel loci in IL-6 (rs1818879) and CRP (rs3093077), increasing risk of depression. Replication is needed by independent groups, targeting these specific variants and interaction with childhood maltreatment on depression risk.

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

Frequency of rare recessive mutations in unexplained late onset cerebellar ataxia.

Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation.

PTPN22 gene regulates natural killer cell proliferation during in vitro expansion.

The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is expressed in hematopoietic tissue and peripheral blood mononuclear cells including natural killer (NK) cells. The rs2476601 single nucleotide polymorphism (SNP) in the PTPN22 gene is an important susceptibility marker for autoimmunity but its role in NK cell biology is not yet clear. The aim of the current study was to evaluate in a cohort of healthy individuals, whether allelic variants of the rs2476601 SNP are associated with NK cell expansion in vitro. The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture. The current study shows that the T variant of the rs2476601 SNP could alter NK vs T-cell balance in vitro and suggests that the PTPN22 gene might have an important immune regulatory role in NK cell function which needs further investigation.

The CD226 gene in susceptibility of type 1 diabetes.

The rs763361 single nucleotide polymorphism (SNP) within the CD226 gene has recently been reported as a novel susceptible locus for type 1 diabetes. The CD226 gene is implicated in the regulation of a number of cells involved in immune mechanisms leading to beta-cell destruction in type 1 diabetes. The aim of the present study was to confirm the association of the CD226 gene with type 1 diabetes in Estonian population. The TT genotype [odds ratio (OR) = 2.29, 95% confidence interval (CI) = 1.25-4.18, P = 0.0071) and the T allele (OR = 1.48, 95% CI = 1.11-1.98, P = 0.0084) of the rs763361 SNP were associated with the risk of type 1 diabetes. The current study replicates the novel association of the rs763361 SNP in susceptibility of type 1 diabetes and supports the CD226 gene as a susceptible candidate locus for type 1 diabetes outside the major histocompatibility complex region.

Cytotoxic T-lymphocyte antigen 4 gene polymorphisms are associated with latent autoimmune diabetes in adults.

BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) molecule is an important regulator of T cell activation involved in the down-regulation of immune response. Polymorphisms within the CTLA-4 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. METHODS: In order to evaluate the impact of allelic variants of the CTLA-4 gene in latent autoimmune diabetes in adults (LADA), the CT60 A/G SNP and the CTBC217_1 C/T SNP were studied in a population of Estonian origin, including 61 LADA patients and 230 controls. RESULTS: It was found that the CT60 GG genotype (p=0.004) and the CTBC217_1 TT genotype (p=0.007) were significant associated with LADA. CONCLUSIONS: Our investigation revealed that not only type 1 diabetes but also LADA is associated with CTLA-4 gene polymorphisms. The role of CTLA-4 gene in the pathogenesis of LADA is open and needs further investigations.

Protein tyrosine phosphatase non-receptor type 22 gene variants at position 1858 are associated with type 1 and type 2 diabetes in Estonian population.

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is considered an important regulator of T-cell activation. Polymorphisms within the PTPN22 gene have been suggested to confer susceptibility to autoimmune endocrine disorders. To evaluate the impact of a functional variation in the PTPN22 gene in type 1 (T1D) and type 2 diabetes (T2D), the PTPN22 C1858T single nucleotide polymorphism (SNP) was studied in the population of Estonian origin, including 170 T1D patients, 244 T2D patients and 230 controls. Using two methods for PTPN22 C1858T detection in parallel, we found that not only T1D but also T2D is associated with the PTPN22 1858T allele. The role of PTPN22 gene in the pathogenesis of T2D is yet unclear and needs further investigation.

HLA alleles as predisposal factors for postmenopausal osteoporosis in a Greek population.

It is well established that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The major histocompatibility complex in humans, known as human leukocyte antigen (HLA) region, is the most polymorphic human genetic system and it is known as a cluster of genetic markers, associated with several diseases. In order to evaluate the contribution of HLA alleles in bone mass loss, polymorphisms in the HLA class I (-A, -B and -Cw) and class II (-DR and -DQ) antigens were studied in 126 postmenopausal women of Greek origin. It was found that HLA-B7 (P= 0.069), -DR15 (P= 0.019) and -DQ6 (P= 0.026) were associated with a lower bone mineral density measured at the forearm. This study shows a significant association between HLA alleles and bone mass loss in the population studied.

Association of vitamin D receptor gene polymorphisms with bone mineral density in postmenopausal women of Hellenic origin.

OBJECTIVES: There are numerous indications that genetic factors play an important role in the pathogenesis of osteoporosis, a common condition characterized by reduced bone mass and increased fracture risk. The vitamin D receptor (VDR) gene has been suggested as a possible candidate gene for the regulation of bone mass but the relationship between VDR polymorphisms and bone mineral density (BMD) is controversial and has not been confirmed by all workers in different ethnic groups studied. METHODS: In order to evaluate the contribution of the VDR alleles in bone mass loss, the BsmI, ApaI and TaqI polymorphisms in the VDR gene were studied in 126 postmenopausal women. RESULTS: It was found that the bb, aa and TT genotypes and the bAT and baT haplotypes were associated with a lower BMD measured at the forearm. CONCLUSIONS: Our analysis reveals a significant association between VDR gene alleles and bone mass in the population studied.