Annals of Human Genetics最新文献

Aims: Thoracic aortic aneurysms and dissections are major causes of sudden cardiovascular death. We aimed to evaluate the clinical significance of the MYLK c.4079G>A, p.(Gly1360Asp) variant in Finnish families with heritable thoracic aortic disease (HTAD) and to assess evidence for a potential founder effect.

Methods: We evaluated the clinical significance and potential founder effect of the missense variant MYLK c.4079G>A, p.(Gly1360Asp) in Finnish families. Eight individuals from four unrelated Finnish families carrying the MYLK c.4079G>A heterozygous variant were recruited. Clinical histories, imaging data, and pedigrees were reviewed. Genetic testing included exome‑based gene panel sequencing or targeted familial variant testing. Variant classification followed the American College of Medical Genetics and Genomics 2015 guidelines.

Results: Thoracic aortic dilatation or aneurysm occurred in 6/8 carriers (75%), with a mean age at diagnosis of 45 years (range 34-67). Ascending aortic diameters ranged from 26-59 mm, most often measured at the aortic root. Aortic dissection occurred in 4/8 (50%) at a mean age of 46 years (range 34-68), including three early‑adult events. Extrathoracic arterial involvement (carotid) was observed in one variant‑positive individual.

Conclusion: The MYLK c.4079G>A, p.(Gly1360Asp) variant was present in six affected individuals from four unrelated families and is enriched in the Finnish population, supporting a founder effect. The MYLK c.4079G>A, p.(Gly1360Asp) variant is associated with early‑adult‑onset, high‑penetrance thoracic aortic disease and substantial dissection risk, underscoring the need for vigilant surveillance and early intervention in affected individuals and at‑risk relatives.

Background: The causes of late onset Alzheimer disease (LOAD) are not known but several recent lines of evidence implicate the adaptive immune system.

Objective: To characterize the adaptive immune system among Midwestern Amish participating in longitudinal studies of aging.

Methods: We immunosequenced the T-cell receptor (TCR) beta chain from genomic DNA of 72 participants, including those with clinically diagnosed LOAD (n = 6), mild cognitive impairment (MCI; n = 16), cognitive impairment but not AD (n = 3), and 35 cognitively unaffected. For a subset of participants, LOAD pathogenesis plasma biomarkers were available.

Results: TCR sequence diversity measured as Simpson's clonality was lower among LOAD+MCI compared with non-LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA-A*03:01 and several HLA-DRB1 alleles were under-represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants, increased p-tau181 was nominally associated with decreased TCR sequence diversity, and the nominal association was independent of age; however, this association did not remain statistically significant after strict correction for multiple testing and the limited sample size precluded formal tests of heterogeneity.

Results: In this limited Midwestern Amish sample, the preliminary TCR diversity trends are consistent with the involvement of the adaptive immune system in LOAD.

Saxby, K. L., S. Stoma, F. Dudbridge, N. J. Samani, M. J. Bown, and C. P. Nelson. 2026. “Evidence of a Protective Effect of Metformin on Abdominal Aortic Aneurysm Risk: Insights From an Observational Study and Mendelian Randomisation Analysis Using Putative Metformin Targets.” Annals of Human Genetics 90, no. 5: 294–302. https://doi.org/10.1111/ahg.70049

In the funding acknowledgement section, the grant reference for the British Heart Foundation Leicester Centre of Research Excellence was stated as being [RE/34/130031]. This grant reference number is incorrect and should be RE/24/130031.

We apologize for this error.

Objectives: From the perspective of uniparental markers, the view of the human prehistoric settlement of America is that it resulted from a single main migration after the Last Glacial Maximum, following a long or short period of genetic isolation in Beringia. Ancient DNA and whole genome analyses have confirmed this view. My objective here is to demonstrate that humans entered America before the LGM and that the documented post-LGM expansions began in South instead of North America.

Methods: In this work, I have reanalyzed all publicly available mitochondrial DNA and Y-chromosome haplogroups in the American population using simple phylogenetic and phylogeographic methodologies.

Results: The arrival of the American settlers occurred more than 30,000 years ago, preceding the LGM. As genomic studies have uncovered, at least two Asian populations contributed to the ancestry of the immigrant population. Low population density and climatic deterioration led to a long period of demographic eclipse, during which small bands of hunter-gatherers made long journeys in search of favorable niches. After the LGM, the climate improved, and demographic expansions occurred in multiple independent centers. The founding and expansion ages of the uniparental haplogroups indicate that these centers were in South America, particularly the Colombian isthmus, the Andean region, the Southern Cone, and the Amazon. Subsequent dispersals occurred in North America, one involving mitochondrial haplogroups A2, C1, and D1, but not B2, and another, of lesser magnitude, represented by the expansion of haplogroups C4c and X2a.

Conclusion: This work offers a previously unexplored model for the colonization of the Americas.