Linkage analysis of multiplex Caribbean Hispanic families loaded for unexplained early‐onset cases identifies novel Alzheimer's disease loci

Abstract

Introduction Less than 10% of early-onset Alzheimer's disease (EOAD) is explained by known mutations. Methods We conducted genetic linkage analysis of 68 well-phenotyped Caribbean Hispanic families without clear inheritance patterns or mutations in APP , PSEN1 , and PSEN2 and with two or more individuals with EOAD. Results We identified 16 (logarithm of odds > 3.6) linked regions, including eight novel loci for EOAD (2p15, 5q14.1, 11p15.1, 13q21.22, 13q33.1, 16p12.1, 20p12.1, and 20q11.21) and eight regions previously associated with late-onset Alzheimer's disease. The strongest signal was observed at 16p12.1 (25 cM, 33 Mb; heterogeneity logarithm of odds = 5.3), ∼3 Mb upstream of the ceroid lipofuscinosis 3 ( CLN3 ) gene associated with juvenile neuronal ceroid lipofuscinosis (JNCL), which functions in retromer trafficking and has been reported to alter intracellular processing of the amyloid precursor protein. Discussion This study supports the notion that the genetic architectures of unexplained EOAD and late-onset AD overlap partially, but not fully.

The Early‐Onset Alzheimer's Disease Whole‐Genome Sequencing Project: Study design and methodology

“…Alleles in known AD genes (eg, APOE and ABCA7 , among others) account for some disease risk variability. African ancestry‐specific AD risk variants in ABCA7 , TREM2 , and other genes have been described by our group and others, 35,41,42 along with loci specific to HI individuals 43–47 . For ABCA7 in particular, a 44 bp deletion is strongly associated with AD in those of AA 35 ancestry and is also present in HI individuals with a high proportion of African global ancestry (41.8%), 48 while other rare truncating and splice altering variants confer risk in the NHW population 49–51 .…”

Early-Onset Alzheimer’s Disease: What Is Missing in Research?

“…It is likely a complex genetic disease caused by a mix of both rare and common variants, as suggested by a heritability study that assessed the genetic contribution in NM-EOAD cases from 32 US Alzheimer's Disease Centers to identify the underlying mode of inheritance [3]. This notion is supported by a recent linkage study among multiplex Caribbean Hispanic families loaded for NM-EOAD [52].…”

Hereditable variants of classical protein tyrosine phosphatase genes: Will they prove innocent or guilty?

“…Dephosphorylation of subunits of these postsynaptic receptors triggers their endocytosis, hence determines synaptic functioning. Reports on the association of PTPN5 gene variants with schizophrenia and cognition ( Pelov et al, 2012 ) and Alzheimer’s disease ( Cheng et al, 2018 ) adds to the evidence connecting STEP with neurologic and neuropsychiatric disorders ( Mahaman et al, 2021 ). Most indications, thus far, come from compelling studies in various animal model systems, and using human post-mortem materials or iPSCs, that reflect schizophrenia ( Carty et al, 2012 ; Pelov et al, 2012 ; Xu et al, 2018 ), Parkinson’s disease ( Kurup et al, 2015 ), Fragile X syndrome ( Chatterjee et al, 2018 ), Huntington’s disease ( Garcia-Forn et al, 2018 ) and stress-related psychiatric disorders ( Yang et al, 2012 ).…”