19 Apr 2019

Genome-wide association studies have turned up some 30 loci linked to Alzheimer’s, yet GWAS still left much of the disease’s heritability unexplained. To find the remaining genes, geneticists have turned to whole-genome and whole-exome sequencing, to family cohorts, and to studies of cell-type specific gene expression. After years of grunt work assembling cohorts and finessing techniques, those approaches are finally bearing fruit, and at the 14th International Conference on Alzheimer’s and Parkinson’s Diseases, held March 27–31 in Portugal’s beautiful capital city of Lisbon, the fruit were on display. Researchers unveiled a trove of new genetic associations, as well as some mechanistic explorations (see Part 2 of this story). 

“We are learning to navigate the post-GWAS world,” Alexandre Amlie-Wolf of the University of Pennsylvania, Philadelphia, summed it up.

Taken together, the new genetic associations emphasize the primacy of APP processing and innate immunity for AD pathogenesis. In fact, talks and posters throughout this five-day conference suggested overall that the way a person’s microglia respond to amyloidosis may determine whether they develop Alzheimer’s disease. Microglia may influence Parkinson’s disease as well, with some talks in Lisbon linking these brain-resident immune cells to PD-risk-gene expression.

Taking a bird’s-eye view to the known genetic associations, it looks as if age-related neurodegenerative disease in general arises due to a failure to respond effectively to cellular damage, said John Hardy of University College London. When a cellular clearance mechanism starts to slow down, the most abundant protein normally cleared in that way—Aβ in AD, α-synuclein in PD, tau in primary tauopathies—will accumulate and fall out of solution, forming aggregates. “Perhaps there’s nothing special about these proteins,” Hardy said. In other words, their specific cellular functions may have little to do with disease pathogenesis. This conclusion is indeed what years of research into their cellular and molecular biology amount to, to the extent that their functions are even understood. Perhaps researchers should instead focus on boosting their clearance to ameliorate disease, Hardy suggested.

The New Gold Standard—Whole-Exome and -Genome Sequencing
The go-to tool for geneticists nowadays is to sequence whole genomes or exomes from large cohorts of people. They often select groups at high risk of disease, such as families with a history of dementia. Unlike GWAS, which find common variants that each contribute little risk, next-generation sequencing can turn up rare variants that confer high risk. The Alzheimer’s Disease Sequencing Project recently identified two new risk genes from whole-exome analysis of 11,000 cases and controls (Aug 2018 news). Although such genes contribute little to population risk, they can illuminate disease pathways. Besides uncovering new genes, whole-exome sequencing finds rare variants in AD’s canonical autosomal-dominant genes that confer less disease risk, for example presenilin 1 mutations associated with late-onset disease. “Whole-exome and -genome sequencing have changed genetic research,” said Christine van Broeckhoven of the University of Antwerp, Belgium.

In Lisbon, Lindsay Farrer of Boston University presented the latest findings from the ADSP. To increase their odds of finding rare genes, the researchers selected “enriched” cases, i.e., people with Alzheimer’s who also had at least one close relative with the disease. They compared whole-exome data from 679 such cases and 5,094 controls. The most robust finding was a single rare missense variant in caspase-7 (CASP7) that associated with AD. For other genes, individual variants missed statistical significance, but the occurrence of several different coding variants linked with disease flagged the locus as a likely risk factor. The genes ANXA5, AARD, IGHJ6, and C1orf173 all passed this “gene-based” association test for AD risk (Zhang et al., 2019). 

Plethora of New AD Genes. Whole-exome sequencing has identified 24 genes with AD-linked coding variants; asterisks indicate the 18 found by ADSP. [Courtesy of Lindsay Farrer.]

What do these genes do? ANXA5 is part of endocytosis and IGHJ6 of immunity, while the functions of AARD and C1orf173 are unknown. CASP7 has been implicated in AD genetics before (Shang et al., 2015). This caspase might contribute to disease by more than one mechanism. Farrer noted that it snips amyloid precursor protein to create a toxic C31 fragment (Fiorelli et al., 2013). In addition, CASP7 helps  activate microglia, again underscoring the importance of these cells in AD (Burguillos et al., 2011; Ayers et al., 2016). 

In another gene-hunting tack reported at AD/PD, ADSP researchers searched whole exomes for rare variants predicted to harm protein function that occurred only among the 5,617 cases, never in the 4,594 controls. This approach unearths high-penetrance variants that are often lost in traditional genetic studies, Farrer explained. The most frequent variant found in this way occurred in 10 AD patients. It is a NOTCH3 missense mutation predicted to strengthen notch3 binding to its ligand, Jagged-1. NOTCH3 signaling is regulated by γ-secretase and BACE1; a common synonymous mutation in the gene was linked to late-onset Alzheimer’s before (Sassi et al., 2018). 

In addition, four participants with AD carried the TREM2 variant Q33X, which causes the bone disorder Nasu-Hakola disease when homozygous. All had late-onset AD and no sign of bone cysts. The researchers also found 10 people with AD who inherited an ATP-binding cassette sub-family D member 4 (ABCD4) haplotype containing three rare variants, and another eight people who inherited multiple variants in both cadherin EGF LAG Seven-pass G-type receptor 1 (CELSR1) and the nearby G2 and S phase-expressed protein 1 (GTSE1). The laminin subunit γ3 (LAMC3) and titin (TTN) genes also sported an unusual number of deleterious variants in AD cases (Patel et al., 2019). 

This is but a list of genes—does their biology support an association with AD? ABCD4 mutations cause vitamin B12 levels to fall, and B12 deficiency is a risk factor for the disease, as are high levels of its substrate, homocysteine (Mar 2002 news; Grarup et al., 2013; Chen et al., 2015). CELSR1 plays a role in brain development and neural tube defects, while GTSE1 regulates microtubule stability. Laminin distribution is perturbed in AD brain, and variants have been linked to onset age (Palu and Liesi, 2002; Saad et al., 2015). Titin, a muscle protein also known as connectin, appears to have no link to AD, but has been shown to form amyloids in vitro (Marsagishvili et al., 2005; Bobylev et al., 2016). 

Altogether, ADSP whole-exome sequencing has added 18 new AD risk genes to the catalogue so far, Farrer said (see image above). Newly found as they may be, they all the same fall into the familiar functional categories of innate immunity, APP processing, vesicle trafficking, and neuronal signaling. “We are filling in genes in well-established pathways that lead to Alzheimer’s disease,” Farrer concluded.

Mining Family Data
By sequencing DNA from families with a disproportionate AD burden, geneticists can also boost their odds of finding rare variants, even in smaller cohorts. In Lisbon, Margaret Pericak-Vance of the University of Miami, Florida, described the ADSP’s Discovery data set, which comprises whole-genome data from 67 such Caribbean Hispanic and 46 Caucasian families. In the former, Pericak-Vance found an A kinase anchor protein 9 (AKAP9) variant that tracked with disease in two families, as well as missense variants in myelin regulatory factor (MYRF) and asparaginase-like 1 (ASRGL1) (Vardarajan et al., 2018). The latter group harbored putatively deleterious variants in nitric oxide synthase 1 adaptor protein (NOS1AP), ATP binding cassette transporter 1 (ABCA1), FISP2, and the long noncoding RNA RP11-433J8 (Beecham et al., 2018). In both ethnic groups, new variants in known AD genes cropped up, as well.

AKAP9 stabilizes microtubules and was previously linked to AD in African American families (Aug 2013 conference news; Logue et al., 2014). ABCA1 is a known AD gene that regulates cholesterol efflux and ApoE levels (Aug 2004 news; Oct 2005 news). The other genes were not previously associated with AD.

Also at AD/PD, Richard Mayeux of Columbia University, New York City, presented two other genes. Whole-exome sequencing of 31 Caribbean Hispanic families nabbed 10 different rare mutations in Sfn2-related CREBBP activator protein (SRCAP) (Vardarajan et al., 2017). Mutations in SRCAP cause Floating-Harbor syndrome, a rare condition marked by stunted growth, and SRCAP protein has been linked to ALS (May 2013 news). SRCAP activates CREB binding protein and helps repair DNA. The second gene, ceroid lipofuscinosis 5 (CLN5), has a missense variant that segregates with AD in these families and causes problems with retromer trafficking (Qureshi et al., 2018). 

In ongoing work, the ADSP is mining a larger whole-genome data set called Discovery Extension, which so far includes 70 Caribbean Hispanic, 58 Caucasian, and 10 African American families, Pericak-Vance said. The team is adding in the genomes from 34 African American families participating in UMiami’s Research in African American Alzheimer’s Disease Initiative as well as 26 families from the Puerto Rican Alzheimer’s Disease Initiative (PRADI). The combined data set has turned up a linkage region on chromosome 5 in African American and Dutch families, as well as a disease link on chromosome 12 near LRRK2 in one African American family. In Puerto Rican families, a region on chromosome 9 near C9ORF72 segregates with disease, but it lacks the infamous repeat expansion. In each case, the genes responsible for the disease association have yet to be identified. The ADSP plans to expand this analysis to nearly 1,000 families, Pericak-Vance said.

In a similar vein, Julie Hoogmartens of the University of Antwerp used whole-genome sequencing of 19 people with early onset AD to search for new recessive familial genes. Working with van Broeckhoven, Hoogmartens found 113 rare homozygous coding variants in them, then narrowed the list to 13 that replicated in an additional 353 cases but did not appear in 903 controls. She winnowed down further to those that were expressed in brain and predicted to be deleterious. This produced four candidate genes: C1ORF194, CCDC136, GFAP, and VWA2, aka Von Willebrand Factor A Domain-Containing Protein 2.

Hoogmartens is particularly interested in VWA2. Found in exosomes, this extracellular matrix protein is considered part of the innate immune response (Dahmer et al., 2016). She verified its Alzheimer’s association in a Belgian cohort of 1,253 and a European cohort of 814 AD patients. Five people carried a homozygous VWA2 variant. Five others carried two different deleterious variants, one from their mother and one from their father, thus damaging both of their VWA2 alleles. This reflects a recessive mode of inheritance, Hoogmartens said. Next, she will examine how the variants affect gene expression, and compare VWA2 protein levels in AD patients and controls.

Tracking Down Elusive Protective Genes
Some populations are known to resist the effects of AD risk genes, and family data can help scientists discover the protective genes at play. In Lisbon, Christiane Reitz of Columbia University noted that even though Caribbean Hispanics run twice the risk of AD as Caucasians, the ApoE4 allele has a less harmful effect on them (Tang et al., 2001; Olarte et al., 2006). To search for modifying factors, Reitz’s colleague Badri Vardarajan examined whole-genome sequence data from healthy elderly ApoE4 homozygotes in two Caribbean Hispanic cohorts. These were WHICAP, a longitudinal community study in New York City, half of whose 6,000 participants are Hispanic, and the Estudio Familiar de Influencia Genética en Alzheimer (EFIGA) cohort of 500 multiplex families from the Dominican Republic, Puerto Rico, and New York City. Both studies follow participants at regular intervals. In 70 homozygous and 130 heterozygous E4 carriers from EFIGA, Vardarajan and Reitz looked for coding variants that appeared in at least 5 percent of cognitively healthy E4 homozygotes but not in people with AD. They verified in the larger WHICAP study that these variants were either absent or less frequent in symptomatic people. This produced 23 variants, which researchers examined in 173 independent AD families and 500 sporadic AD cases for correlations with either AD risk or age of onset. They came up with two that tracked with onset: BMP1 and NBEAL1.

NBEAL1 had the largest effect, delaying symptoms. The neurobeachin-like 1 protein is involved in vesicle trafficking and receptor signaling and correlates with white-matter hyperintensities (Jian et al., 2018; Traylor et al., 2016). The gene resides near an age-of-onset ADGC GWAS hit (Naj et al., 2014). Reitz said the groups are investigating what NBEAL1 does.

Jeffery Vance, University of Miami, is also pursuing genes that protect against ApoE4; however, he is using a different strategy and an additional ethnic group. Like Hispanics, African Americans seem partially resistant to the deleterious effects of an E4 allele (Farrer et al., 1997; Evans et al., 2003; Weuve et al., 2018). To track down the gene(s) responsible, Vance exploits the fact that African American and Hispanic gene pools began to mix only about 300 years ago, owing to colonialism and slavery. In the U.S., Hispanic populations typically carry a mixture of European, African, and Native American genes, with the former predominating, while African Americans carry genes from several African tribes as well as some European DNA (Zakharia et al., 2009). Different modern groups carry distinct proportions. For example, Haitians tend to have mostly African ancestry, while Puerto Ricans have mostly European.

This allowed Vance to ask if protective associations were the result of local ancestry, i.e., a variant that lies near ApoE and thus is inherited with it, or global ancestry, i.e., some separate factor that was widespread among a particular group because of the part of the world in which they arose. The researchers analyzed 1,766 cases and 3,730 controls of African American ancestry, and 220 cases and 169 controls of Puerto Rican ancestry. For both ethnic groups, the analysis strongly suggested that local, not global, ancestry was modifying ApoE risk. In other words, ApoE4 alleles on an African local background conferred less risk than ApoE4 alleles on a European local background, no matter which ethnic group a person belonged to (Rajabli et al., 2018). 

Vance is now trying to track down the protective variant by identifying sequence differences in this local ancestry region and correlating them with functional changes in gene expression or pathology, using postmortem brain samples from homozygous ApoE4 carriers from each population. The researchers have found more than 700 sequence differences in the 2 megabase region around ApoE, all of them noncoding. Because the TOMM40 gene occurs near ApoE and has been linked to differences between African and European AD risk before, Vance investigated its effect (Roses et al., 2014; Yu et al., 2017). However, in Lisbon he said that he found no relationship between TOMM40 alleles and AD risk in African Americans, although among people with European local ancestry and an ApoE3 allele, the very long poly-T repeat of TOMM40 did correlate with lower risk. In answer to audience questions, Vance said he still has not identified the variant that protects against ApoE4, but he believes it will turn out to be a regulatory change in ApoE expression.—Madolyn Bowman Rogers

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1. Expression, Expression, Expression—Time to Get on Board with eQTLs 19 Apr 2019
2. Largest AD Whole-Exome Study to Date Finds Two New Risk Genes 17 Aug 2018
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External Citations

1. Floating-Harbor syndrome
2. Research in African American Alzheimer’s Disease Initiative

Further Reading

News

1. Paper Alerts: Massive GWAS Studies Published 2 Mar 2019
2. Searching for New AD Risk Variants? Move Beyond GWAS 4 Aug 2017
3. Do African-Americans Have More, or Different, Alzheimer’s Disease? Too Little Data to Tell 26 Oct 2018
4. Do Alzheimer’s Biomarkers Vary by Race? 11 Jan 2019